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. 2023 Mar 22;35(2):91–99. doi: 10.5021/ad.22.175

The Tumor Immune Microenvironment in Cutaneous Squamous Cell Carcinoma Arising in Organ Transplant Recipients

Catherine Zilberg 1,✉, James Guy Lyons 2, Ruta Gupta 3, Angela Ferguson 2, Diona Lee Damian 1,4
PMCID: PMC10112371  PMID: 37041702

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy in immune-suppressed organ transplant recipients (OTRs). Whilst rates of other malignancies (both cutaneous and non-cutaneous) are elevated in this population, the increase is far less striking. This suggests that cSCC must be a highly immunogenic tumor. The tumor immune microenvironment is altered in cSCC from OTRs. It has reduced anti-tumor properties and instead provides an environment that facilitates tumor growth and survival. Understanding the composition and function of the tumor immune microenvironment in cSCC from OTRs is useful for prognostication and therapeutic decisions.

Keywords: Carcinoma, Skin neoplasms, Squamous cell, Transplantation immunology

EPIDEMIOLOGY OF CUTANEOUS SQUAMOUS CELL CARCINOMA IN ORGAN TRANSPLANT RECIPIENTS

Cutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous malignancy. Rates in organ transplant recipients (OTRs) are 60 to 250 times that in the general population1,2,3,4. Following an initial skin cancer diagnosis, 50% of OTRs developed a second tumor within 2 years4. There is a tendency for tumors, especially cSCC, to develop at sites with pre-existing keratotic lesions5. It is unclear whether new keratinocyte cancers are more likely to appear adjacent to sites of previously excised primary tumors.

In lung transplant recipients, the risk of developing a subsequent cSCC four years after initial cSCC is 86%6. cSCC from OTRs behave in a clinically aggressive manner; cancers are more likely to be invasive, display perineural and lymphovascular invasion, and require chemotherapy or radiation therapy7,8. Head and neck cSCC from OTRs display greater recurrence rates than those observed in immunocompetent patients9. In general, risk factors for the development of post-transplantation cSCC are similar to those for the general population (i.e., age, male sex, prior skin cancer)3,6. Increased time after transplant is associated with risk3. Risk profile differs based on transplant type2. Heart/lung recipients have the greatest increase in cSCC risk followed by kidney recipients and lastly by liver transplant recipients2,6. This is likely a reflection of the decreasing cumulative immunosuppressive dosages administered to each group respectively2.

The literature is divided on whether particular immunosuppressive medications confer increased or reduced risk of developing cSCC in OTRs6,10,11. Metastatic cSCC is considered more common in OTRs. However, a recent systematic review has shown discrepancies with this statement12. Whilst pooled metastasis risk is greater in OTRs, the risk per individual tumor appears to be similar between OTRs and immunocompetent patients12. Risks of bias from more frequent follow-up in OTRs makes analysis of these results difficult12.

Given the differing prevalence and contrasting clinical behavior of the same disease in immunocompetent and immunosuppressed patients, it is plausible to hypothesize that the tumor immune microenvironment will vary between these two groups.

The tumor immune microenvironment is altered in OTRs. We conducted a review of the literature with the aim of summarizing features of the immune microenvironment in cSCC from OTRs and how it differs from cSCC in immunocompetent individuals. We have focused on the organ transplant population as limited data is available for populations with other etiologies for their immunosuppression.

IMMUNE INFILTRATE QUANTITY

cSCC from immunocompetent patients demonstrates an elevated inflammatory infiltrate compared to healthy human skin13. There is a significant increase in immune infiltrate from normal skin to benign hyperproliferative lesions (i.e., seborrheic keratosis, verruca vulgaris, hypertrophic lichen planus) to actinic keratosis and cSCC13,14. cSCC from OTRs also demonstrated the presence of an immune infiltrate (Table 1)15. However, this infiltrate is reduced compared to that in immunocompetent patients15,16.

Table 1. Summary of the differences in the tumour immune microenvironment composition between cSCC from OTRs versus immunocompetent patients.

Immune infiltrate component OTR cSCC vs. immunocompetent cSCC
Quantity of immune infiltrate Reduced15,16
CD4+ T cells Reduced16,25,26
CD4+ T helper 1 T cells Reduced25
CD4+ FOXP3+ T regulatory cells Increased21,30
Reduced15,25
CD8+ T cells Reduced20,21,22,24
Equivalent25
Increased26
Cytotoxic CD8+ T cells Reduced20
Naïve CD8+ T cells Reduced20
Regulatory CD8+ T cells Equivalent20
Exhausted CD8+ T cells Equivalent20
Tumour associated macrophages Equivalent (reduced accumulation early in tumorigenesis)35
Reduced16
Dendritic cells Equivalent37
Reduced15,38
B cells Reduced16,22
Ki67 staining on tumour cells Increased–diffuse staining21
IL-22/IL-22R expression Increased–diffuse staining21
PD1 expression Increased44
Equivalent43
PDL1 expression Equivalent43,45
PDL2 expression Equivalent45
Lag3+ CD8+ cells Reduced26
OX40 Expession Increased30
B7 H3 expression Equivalent43
Reduced (in HIV+ group)43
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cSCC: cutaneous squamous cell carcinoma, OTRs: organ transplant recipients, HIV: human immunodeficiency virus.

IMMUNE INFILTRATE IN CUTANEOUS SQUAMOUS CELL CARCINOMA

T lymphocytes

T lymphocytes are characterized by the presence of a T-cell receptor (TCR). CD8+ and CD4+ cells are two broad categories of T lymphocytes. There are many functional subtypes of T cells based on gene expression profiles. These subtypes have different effects on tumor growth and responses to treatment. Most studies analyzing the immune infiltrate in cSCC from OTRs have characterized only a limited number (or none) of these subtypes.

CD8+ T lymphocytes

CD8+ T lymphocytes may function as major effectors of the anti-tumor immune response17. However, there are several differentiation states of CD8+ T lymphocytes, each of which may have a variety of effects on tumor growth. In general, greater tumoral infiltration of CD8+ lymphocytes is associated with favorable prognosis in many (but not all) malignancies18,19. Most studies have identified a reduction in CD8+ T lymphocytes in OTR-associated cSCC compared to levels in immunocompetent patients2,16,20. Immunohistochemical (IHC) analysis demonstrated reduced CD8+ T lymphocytes in cSCC arising in immune suppression21. However, tumoral CD8+ T cell levels were still higher than the density of these cells in surrounding, unaffected skin21. Similar results were identified in recent studies by Frazzette et al.20 and Strobel et al.16. In a study by Datta et al.22 both CD3+ and CD8+ T lymphocytes were reduced in the tumor center and the invasive margin of cSCC from OTRs compared to non-transplant patients. cSCC precursor lesions (Bowen’s disease) demonstrated reduced T lymphocytes only in the tumor center when compared to immunocompetent controls22. Frazzette et al.20 additionally analyzed the functional phenotypes of CD8+ T lymphocytes in cSCC. This is the sole study to do so to date. RNA expression profiling was utilized to characterize and define CD8+ T lymphocyte subtypes20. These include: cytotoxic (PRF1, GZMA, GZMB, IFNγ), naïve (CCR7, LEF1, TCF7, IL7R), exhausted (BTLA4, CTLA4, PDCD1, LAG3), and regulatory (FOXP3, STAT3, TNFRSF4, TNFRSF9) CD8+ T lymphocytes20. Transplant-associated cSCC had lower proportions of cytotoxic and naïve T lymphocytes20. Immunocompetent and immunosuppressed cSCC had similar numbers of exhausted and regulatory CD8 T cells20. The identification of CD8+ FOXP3+ T lymphocytes was a novel finding in this study20. These cells have been identified and characterized in other malignancies23. FOXP3+ CD8+ T lymphocytes are termed CD8+ regulatory cells23. Chaput et al.23 identified CD8+ FOXP3+ cells in peripheral blood and in colorectal cancer tissue. These cells have suppressive capacity by inhibition of the effector CD4+ T cell proliferation and of Th1 cytokine production23.

Clark et al.24 investigated possible mechanisms for the observed decrease in CD8+ T lymphocytes in OTR-associated cSCC. E-selectin is an endothelial-leukocyte adhesion molecule which acts as a ligand for CLA+ CD8+ T lymphocytes24. The authors identified reduced levels of E-selectin in the cSCC tumor vasculature of immunosuppressed patients24. Therefore, this may explain reduced migration of CD8+ T lymphocytes to the tumoral infiltrate24.

CD8+ effector T cell clones may not be expanding adequately in the OTR microenvironment20. RNA sequencing and TCR sequencing was performed on isolated cSCC CD8+ T lymphocytes from OTRs and immunocompetent patients20. Albeit a small study (5 cSCC from immunocompetent patients and 6 from OTRs) a significantly reduced heterogeneity of TCR clones in the OTR group (mean 544 vs. 1,140) was demonstrated20. There was also significantly reduced expansion of the top 10 most prevalent TCR clonotypes in the OTR group20.

Few studies have found contradictory results to those described above. Kosmidis et al.25 identified similar CD8+ T lymphocytes levels across OTR-associated cSCC and tumors from immunocompetent patients. Interestingly, Glaun et al.26 demonstrated increased density of CD8+ T lymphocytes in the OTR cSCCs compared to levels in immunocompetent controls by multispectral imaging.

CD4+ T lymphocytes

A high CD4+ T lymphocyte infiltrate in cSCC from immunocompetent patients has been demonstrated27. CD4+ T lymphocytes are more prevalent than CD8+ T lymphocytes in cSCC27. In general, CD4+ T lymphocytes appear to be reduced in OTRs compared to immunocompetent patients25,26. Kosmidis et al.25 found reduced CD4 mRNA levels in OTR-associated SCC compared to that in immunocompetent SCC. Glaun et al.26 also found reduced stromal and tumoral CD4 cells. IHC analysis by Strobel et al.16 demonstrated reduced levels of CD4+ T cells in OTR-cSCC. This difference reached significance only at the invasive margin of the tumor16.

CD4+ T helper 1 lymphocytes

OTRs appear to have reduced tumoral CD4+ Th1 cells25. There are reduced Th1 associated cytokines in OTR-associated cSCC25. T-bet (a Th1 specific transcription factor) and IFNγ (a promoter and effector of the Th1 response) are reduced in cSCC from OTRs25.

CD4+ FOXP3+ T lymphocytes

FOXP3 is a transcription factor involved in the regulation and function of T regulatory cells. Elevated infiltration of T regulatory cells is correlated with a poorer prognosis in some malignancies28. In a large study of immunocompetent cSCC, higher tumoral T regulatory infiltration was correlated with development of metastatic disease29. The consensus is that cSCC in OTRs has greater levels of CD4+ FOXP3+ T regulatory cells than tumors from immunocompetent patients21,30. Zhang et al.21 performed IHC analysis of FOXP3 from immunocompetent and immunosuppressed cSCC. Whilst the absolute number of FOXP3 positive cells were similar in both groups the proportion of FOXP3+ to CD8+ T cells was approximately double in OTR cSCC21. Clark et al.24 identified large numbers of FOXP3+ T regulatory cells in the OTR immune infiltrate. Feldmeyer et al.30 identified greater FOXP3 mRNA in OTRs, as well as increased expression of mRNAs for cytokines and other proteins associated with T regulatory cells including IL-2 receptor, TGFβ1, RUNX3, and CXCR4. A minority of studies have demonstrated decreased FOXP3 levels in cSCC from OTRs15,25.

Myeloid derived suppressor cells

Myeloid derived suppressor cells (MDSCs) are immature myeloid cells that are characterized by the ability to suppress immune responses and expand during carcinogenesis31. They facilitate tumor growth and survival31. This has been shown in multiple cancer types32. MDSC function is poorly described in cSCC from both immunocompromised and immunocompetent patients. Seddon et al.33 performed IHC analysis on cSCC from immunocompetent and immunosuppressed (OTR) patients. Tissue was stained with antibodies to CD8 and the neutrophil marker CD66b33. The immunosuppressed population had significantly higher staining for CD66b33. This is not a specific marker, identifying many granulocytes (neutrophils, eosinophils and granulocytic MDSCs)33. The authors postulate that cSCC in OTRs may have higher MDSCs33.

Macrophages and dendritic cells

There is paucity of data in the literature regarding macrophage and dendritic cell (DC) infiltration in cSCC from OTRs. There are several subtypes of macrophages that infiltrate tumors. Traditionally, tumoral macrophages have been broadly classified into M1 and M2 tumor associated macrophages (TAMs)34. M1 macrophages are considered to have anti-tumor functions34. They exert their function by direct cytotoxicity and by participating in antibody-dependent cell-mediated cytotoxicity34. M2 macrophages have a pro-tumorigenic effect by expressing substances with growth, invasion, metastasis and angiogenesis promoting capabilities34. However, this is likely an oversimplified classification. Overall, there are increased macrophages in cSCC from OTRs and immunocompetent patients compared to normal skin34. Levels may be higher in cSCC from immunocompetent patients than in cSCCs from OTRs.

Cyrus et al.35 investigated the density and polarization of TAMs in cSCC, cSCC-in situ and normal skin from OTRs and non-transplant patients. IHC analysis of CD68, CD40 and Arg1 was utilised35. CD68 is a glycoprotein heavily expressed by macrophages and phagocytic monocytes. It is not specific for macrophage/monocyte subtypes. Broadly, CD40 is a marker associated with M1 macrophages and Arg1 is associated with M2 macrophages35. Higher TAM numbers were identified peritumorally and intratumorally in cSCC and cSCC-in situ from both OTRs and non-transplant patients compared with normal skin35. cSCC-in situ from OTRs had reduced TAMs in the intratumoral infiltrate compared with non-transplant patients35. TAMs from all tumors displayed both M1 and M2 activation, however, M2 levels were lower in cSCC from OTRs35. In summary, TAMs are present in cSCC and cSCC-in situ at higher densities than in healthy skin35. Iatrogenic immunosuppression in OTRs results in somewhat reduced TAM accumulation early in carcinogenesis35. In another study, CD68+ staining was significantly reduced in cSCC from OTRs compared to lesions from immunocompetent patients16.

DCs are "professional" antigen presenting cells which present antigen in complex with MHC II to T cells. There are several subtypes of DCs located in the skin. These include Langerhans cells, plasmacytoid DCs and dermal myeloid DCs36. Both normal skin and pathological states have infiltration of these cell types36. Gibson et al.37 used the (non-specific) Leu-6 antibody to identify Langerhans cells (LC) in cSCC, BCC, dysplastic lesions and viral warts from renal transplant recipients. There was no significant difference between LC number in normal skin from renal transplant versus immunocompetent patients37. There were significantly reduced numbers of LCs from SCC, BCC, dysplastic lesions and viral warts compared to normal skin37. In another study, LC were similar in OTR and immunocompetent cSCC38. CD11c+ myeloid DCs were reduced in the peritumoural stroma of cSCC from OTRs compared to immunocompetent patients38.

Mühleisen et al.15 demonstrated reduced CD123+ plasmacytoid DCs in cSCC from OTRs. Plasmacytoid DCs are a rare subtype of DC, identified by expression of CD123 on their cell surface39. A primary function of these cells is secretion of type 1 interferons39. The effect of these cytokines includes stimulation of polarization of CD4+ cells to Th1 and increasing proliferation and cytotoxicity of CD8+ T cells39. These findings align with the evidence of reduced CD4+ Th1 cells25 and reduced CD8+ cells in OTR-associated cSCC20.

B cells

There is very limited data regarding B cells in the infiltrate of cSCC—both for immunocompetent and immunosuppressed patients. In one study, IHC analysis demonstrated reduced B cells in the OTR group as defined by intensity of CD20 staining on IHC analysis16. Datta et al.22 used CD20 IHC (as a surrogate for tertiary lymphoid structures). There was significantly reduced CD20 staining in cSCC from OTRs compared to immunocompetent controls22.

Tumor proliferation profile, cytokines and chemokines

Ki67 is a marker of proliferation. In cSCC from OTRs Ki67 expression differs to that observed in cSCC from immunocompetent patients21. In immunocompromised patients Ki67 staining (of keratinocytes) is significantly elevated (with more diffuse expression) compared to that observed in immunocompetent patients21.

In addition, the staining pattern is diffuse within the tumor, rather than present solely at the invasive front of the cSCC21. This demonstrates greater proliferative capacity of cSCC in OTRs21. IL22 is a cytokine which has been implicated in the pathophysiology of benign hyperproliferative disorders such as psoriasis40. IL22 is a major effector cytokine of the Th22 axis. IL22 is expressed at elevated levels in cSCC from both immunocompetent and OTR patients compared with normal skin21. IL22 binds to the IL22 receptor (IL22R), leading to JAK/STAT signaling. The IL22R is expressed at elevated levels on keratinocytes in cSCC (from immunocompetent patients and OTRs) compared to normal skin21. The expression pattern of this receptor differs between OTRs and immunocompetent patients21. In immunocompetent cSCC IL22R is located only at the leading (invasive) front of the tumor, whereas in cSCC from OTRs the IL22R is found diffusely expressed within the tumor21. Functional studies have demonstrated IL22 signaling facilitates proliferation of cSCC cell lines21.

Cancer associated fibroblasts

There are no studies examining the presence and role of cancer associated fibroblasts (CAFs) in cSCC in OTRs. In cSCC from immunocompetent patients, CAFs have been shown to differ both morphologically and functionally from normal dermal fibroblasts41. CAFs from cSCC have an undifferentiated morphology, greater migratory potential, stimulate increased procollagen 1 production and lead to greater invasion in vitro41.

Immune checkpoint proteins

There is a positive association between PDL1 expression and high-risk features in cSCC42. These include higher histological grade, greater diameter and increased tumor thickness in immunocompetent patients42.

Overall, PD1/PDL1 expression is similar in cSCC from OTRs and immunocompetent controls. Varki et al.43 assessed the expression of PD-L1, B7-H3 and PD-1 in cSCC from immunocompetent and immunosuppressed patients. The immunosuppressed patient population included OTRs, HIV+ patients and those with hematological malignancies43. The only significant difference in immune checkpoint expression between immunocompetent and immunosuppressed patients was in expression of B7H3 which was lower in immunosuppressed patients, especially in the HIV+ group43. Otherwise, the authors noted no differences between PD-L1 expression on tumor cells or tumor infiltrating lymphocytes (TILs), and in PD1 expression by CD8+ and CD4+ T cells43. Stevenson et al.44 identified significantly increased expression of PD1 in cSCC from OTRs compared to immunocompetent cSCC.

Amoils et al.45 performed an IHC study assessing PDL1 expression and TIL infiltration in locally invasive and metastatic cSCC of the head and neck region. Their study included 25% of lesions from immunocompromised patients45. They did not identify an association between grade of PDL1 staining with immune status45. In summary, expression of PD1/PDL1 and PDL2 appears similar from OTR and immunocompetent cSCC. Some studies have described increased PD1 expression in OTR-cSCC.

OX40 is a receptor expressed on several cell types including activated CD4+ and CD8+ T lymphocytes46. When stimulated, this receptor promotes effector T cell survival and decreases the inhibitory potential of T regulatory cells46. Feldmeyer et al.30 identified the novel finding that OX40 is also elevated in OTR cSCC compared to that observed in immunocompetent patients. There is increased gene expression of OX40 in organ transplant cSCC compared to tumors from immunocompetent patients30. These results were further confirmed with IHC analysis30. In vitro agonism of this receptor leads to increased effector T cell function and suppressed T regulatory cell function29.

Lag3 is a transmembrane protein, the expression of which is induced on CD4+ and CD8+ T lymphocytes upon antigen stimulation47. It is considered to facilitate an immunosuppressive response48. Wu et al.49 performed an IHC analysis on advanced cSCC from immunocompetent patients examining expression of Lag3. Lag 3 was identified in most tumors49. Only one study has assessed Lag3 expression in cSCC from OTRs26. It identified reduced CD8+ Lag3+ cells in cSCC from OTRs26.

TREATMENT WITH IMMUNE CHECKPOINT INHIBITORS

There are currently no prospective clinical trials investigating the safety and efficacy of immune checkpoint inhibitors (ICIs) in cSCC in OTRs. Review articles have summarized results from case reports, case series and retrospective studies. Whilst efficacy is moderately high, there is a very high rate of graft rejection. Portuguese et al.50 conducted a large systematic review of ICI use in solid OTRs for a range of malignancies. In their study, data from 22 patients with cSCC were available with kidney or liver transplant50. The overall response rate (ORR) was high for this group at 68.2%, with a complete response in 31.8% of patients50. Factors associated with increased ORR include greater time from transplant and reduction in immunosuppressive regimen50. Graft rejection occurred in 41.2% of patients, and graft failure in 23.5%50.which is higher than standard rates of chronic rejection51,52.

Murakami et al.53 conducted a systematic review on safety and efficacy of ICIs for treatment of solid organ malignancies in kidney transplant recipients. Twenty-four patients receiving an ICI had cSCC53. For cSCC the ORR was 28.9%, with a complete response of 7%53. Graft rejection was experienced by 37.5% of cSCC patients on ICI53. Graft rejection occurred within weeks of commencing ICI therapy53. mTOR inhibitor use was possibly associated with reduced rejection rate53. In a recent review of 7 cases by Tsung et al.54, 7 OTRs with metastatic head and neck cSCC received cemiplimab or pembrolizumab after minimization of calcineurin inhibitor dose or switch to mTOR inhibitor. ORR was 57%, with 1 complete response and 3 partial responders54. Prophylactic prednisolone preserved allograft function and diminished adverse events54.

SUMMARY

In summary, evidence suggests that the tumor immune microenvironment in cSCC from OTRs differs from that in immunocompetent patients. The limited number of studies in the literature creates difficulties in drawing concrete conclusions. Most studies utilized IHC to investigate staining patterns of relatively few (and often non-specific) antibodies. There is limited data on immune subtypes beyond broad classes of immune cells. Overall, there is a reduced immune infiltrate in cSCC from OTRs compared to the quantity of infiltrate in immunocompetent cSCC. There is an overall reduction in CD8+ T cells and CD4+ T cells. Most studies identify higher CD4+ FOXP3+ T cell levels, and the presence of a CD8+ T regulatory cell population. There are similar numbers of TAMs across both groups. Certain subtypes of DCs appear reduced in OTR cSCC, particularly CD123 plasmacytoid DCs. OTR cSCC has a higher Ki67 index and diffuse IL22/IL22R expression, reflected in its greater proliferation and more aggressive clinical behavior. There is increased expression of cytokines associated with the T regulatory response. Immune checkpoint markers are present in cSCC from OTRs. Expression of PD1/PDL1 and PDL2 is similar in OTR cSCC and immunocompetent cSCC. OTRs have reduced Lag3 expression on CD8 cells, possibly reduced B7H3 levels and increased expression of OX40. There is limited data on B cell expression and on the presence and role of CAFs in OTR cSCC. Therefore, the immune microenvironment in OTR cSCC differs from that in immunocompetent cSCC. There appears to be a reduced anti-tumor immune response and an increased immunosuppressive environment.

LIMITATIONS AND CONCLUSION

There are limited numbers of studies characterizing the immune microenvironment in cSCC in OTRs. Greater understanding of this topic is important due to the increasing numbers of transplants performed, the greater post-transplantation survival rate (particularly early graft survival) and the very high incidence of cSCC in this population55. Understanding the tumor immune microenvironment in this population may shed light onto disease specific features, such as prognosis and response to treatment. It may also further the understanding of the function of immune cell types on tumor biology. Most studies examining the tumor immune microenvironment in cSCC from OTRs have used methods including immunohistochemistry, immunofluorescence or flow cytometry with very limited numbers of markers. Given the complexity and variability of immune cells, many studies have used non-specific antibodies to characterize cell types. There is scope and need for further research in this field.

Footnotes

CONFLICTS OF INTEREST: The authors have nothing to disclose.

FUNDING SOURCE: None.

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