Squamous cell carcinomas escape immune surveillance via inducing chronic activation and exhaustion of CD8+ T Cells co-expressing PD-1 and LAG-3 inhibitory receptors.
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.
Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Ameet K
AK
Mishra
Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Tanya
T
Kadoishi
Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Xiaoguang
X
Wang
Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Emily
E
Driver
Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA.
Zhangguo
Z
Chen
Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Xiao-Jing
XJ
Wang
Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA.
Jing H
JH
Wang
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D016827:CD8 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D019610:Cytoprotection; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D051901:Smad4 Protein; D013997:Time Factors; D047368:Tumor Burden; D019139:Tumor Escape / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; D000074322:Antineoplastic Agents, Immunological; D016827:CD8 Antigens; C117307:KRAS protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016283:Proto-Oncogene Proteins p21(ras); D000093322:Lymphocyte Activation Gene 3 Protein
LAG-3; PD-1; Smad4 loss; immune evasion; squamous cell carcinoma