Abstract
Squamous cell carcinoma (SCC) is the second commonest type of skin cancer. Moreover, about 90% of head and neck cancers are SCCs. SCCs develop at a significantly higher rate under chronic immunosuppressive conditions, implicating a role of immune surveillance in controlling SCCs. It remains largely unknown how SCCs evade immune recognition. Here, we established a mouse model by injecting tumor cells derived from primary SCCs harboring KrasG12D mutation and Smad4 deletion into wild-type (wt) or CD8−/− recipients. We found comparable tumor growth between wt and CD8−/− recipients, indicating a complete escape of CD8+ T cell-mediated anti-tumor responses by these SCCs. Mechanistically, CD8+ T cells apparently were not defective in infiltrating tumors given their relatively increased percentage among tumor infiltrating lymphocytes (TILs). CD8+ TILs exhibited phenotypes of chronic activation and exhaustion, including overexpression of activation markers, co-expression of programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), as well as TCRβ downregulation. Among CD4+ TILs, T regulatory cells (Tregs) were preferentially expanded. Contradictory to prior findings in melanoma, Treg expansion was independent of CD8+ T cells in our SCC model. Unexpectedly, CD8+ T cells were required for promoting NK cell infiltration within SCCs. Furthermore, we uncovered AKT-dependent lymphocyte-induced PD-L1 upregulation on SCCs, which was contributed greatly by combinatorial effects of CD8+ T and NK cells. Lastly, dual blockade of PD-1 and LAG-3 inhibited the tumor growth of SCCs. Thus, our findings identify novel immune evasion mechanisms of SCCs and suggest that immunosuppressive mechanisms operate in a cancer-type specific and context-dependent manner.
Highlights
Squamous cell carcinomas (SCCs) are cancers that derive from stratified epithelia present in the skin and the lining of other organs such as aerodigestive tract
Our results showed that both CD8+ and CD4+ tumor infiltrating lymphocytes (TILs) co-expressed inhibitory receptors, programmed cell death 1 (PD-1) and lymphocyte activation gene-3 (LAG-3), and dual blockade of PD-1 and LAG-3 significantly suppressed the tumor growth of SCCs
Given that CD8+ T cells play a dominant role in anti-tumor immunity, we investigated whether the absence of CD8+ T cells affects the tumor growth by transplanting KRS-SCC tumor cells into CD8−/− recipients
Summary
Squamous cell carcinomas (SCCs) are cancers that derive from stratified epithelia present in the skin and the lining of other organs such as aerodigestive tract. UV-induced skin cancers frequently harbor RAS mutations [3, 4]. Skin SCCs and tobacco-related HNSCCs often harbor heterozygous loss of Smad, and Smad downregulation is an early event in SCC development [6,7,8]. Mice with the deletion of Smad in stratified epithelia develop spontaneous SCCs in the skin, oral cavity, and forestomach [6, 9, 10]. Recent studies www.impactjournals.com/oncotarget showed that combining KrasG12D mutation and Smad loss in keratin 15-expressing (K15+) stem cells resulted in rapid development of aggressive SCCs that are highly metastatic [11]. It remains largely unknown how SCCs evade immune recognition
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