Pervasive loss of antigen presentation in solid tumors driven by loss of HLA class I expression.
Authors: Sarabjot Pabla, Heidi Chwan Ko, Maria-Fernanda Senosain, Hardik Parikh, R.J. Seager, Erik Van Roey, Shuang Gao, Yamuna Pulivendula, Paul DePietro, Mary K. Nesline, Durgapras Dash, Jeffrey M. Conroy, Stephanie B. Hastings, Kyle C. Strickland, Rebecca A. Previs, Eric A. Severson, Marcia Eisenberg, Brian Caveney, Taylor J. Jensen, Shakti H. Ramkissoon
Journal: Journal of Clinical Oncology (2024)

e14654 Background: Human Leukocyte Antigens (HLA) play a key role in inducing responses to immune checkpoint inhibitor (ICI) therapy. HLA class I (HLA-I) expression is essential for antigen presentation in cancer cells and its loss leads to immune evasion. Expression of HLA-II shows presence of adaptive immune response via antigen presenting cells. To investigate the complex interplay of HLA class I/II in solid tumors, we study the landscape and association of several HLA phenotypes with biomarkers of tumor response and resistance to ICIs in a large pan-cancer cohort. Methods: A real-world cohort of 24,186 solid tumors was assessed by an immune expression profiling assay of 395 genes that were background subtracted, normalized, and ranked yielding a percentile rank value [0-100]. HLA Class I and class II expressions were estimated as average expression of HLA-A, HLA-B, HLA-C genes, and HLA HLA-DP, HLA-DQ, HLA-DR genes, respectively. Both HLA classes were labelled as high (≥66), moderate (≥33 &amp; &lt;66) or low (&lt;33). We studied the distribution of HLA I/II phenotype defined as I hi /II hi comprised hot tumors with no loss of HLA-I and I lo /II hi defines immune evasion via loss of HLA-I in hot tumors. I hi /II lo phenotype comprises less inflamed tumors with high HLA-I expression and I lo /II lo comprises of cold tumors. We also performed differential expression of ICI targets including PD-1, PD-L1, LAG-3, TIM3 and expression-based signatures of inflammation and cell proliferation. Results: Loss of HLA-I expression was observed in 44.1% (n= 10669) of all solid tumors with most frequent loss observed in prostate (55%, n=450) cancer. Similarly, loss of HLA-II expression was observed in 34.7% (n=8396) of solid tumors with highest loss observed in neuroendocrine (59%; n=345) cancers. 49% of all tumors presented with four HLA-phenotypes, where 17.9% (n=4332) were characterized by I lo /II lo phenotype. I hi /II lo was present in 13% (n=3127) of all tumors. Both I hi /II hi and I lo /II hi phenotypes were significantly (p&lt;0.001) associated with increased tumor inflammation. Other ICI targets such as PD-L1, TIM3, CTLA4 and LAG3 were significantly (p&lt;0.001) overexpressed in this immune evasion phenotype compared to other phenotypes. Conversely, I lo /II lo phenotype was significantly associated with cold tumors (p&lt;0.001), hinting at lack of adaptive immune response in these tumors. Conclusions: This study offers insight into pervasive loss of antigen presentation via HLA expression. Concurrent loss of HLA Class I expression with increased class II expression and additional ICI target co-expression is a potential immune escape mechanism in immunologically active solid tumors. Distinct and significant association of these MHC phenotypes with tumor inflammation, checkpoint markers and PD-L1 highlight the potential use of comprehensive immune profiling for further studying combination strategies to correct soft loss of HLA-I and ICI therapies.