ABSTRACT
BACKGROUND: Whereas human leukocyte antigen (HLA) class I mutation-associated neoantigen burden has been linked with response to immune checkpoint blockade (ICB), the role of HLA class II-restricted neoantigens in clinical responses to ICB is less studied. We used computational approaches to assess HLA class II immunogenic mutation (IMM) burden in patients with melanoma and lung cancer treated with ICB. PATIENTS AND METHODS: We analyzed whole-exome sequence data from four cohorts of ICB-treated patients with melanoma (n = 110) and non-small-cell lung cancer (NSCLC) (n = 123). MHCnuggets, a neural network-based model, was applied to estimate HLA class II IMM burdens and cellular fractions of IMMs were calculated to assess mutation clonality. We evaluated the combined impact of HLA class II germline genetic variation and class II IMM burden on clinical outcomes. Correlations between HLA class II IMM burden and density of tumor-infiltrating lymphocytes were computed from expression data. RESULTS: Responding tumors harbored a significantly higher HLA class II IMM burden for both melanoma and NSCLC (P ≤ 9.6e-3). HLA class II IMM burden was correlated with longer survival, particularly in the NSCLC cohort and in the context of low intratumoral IMM heterogeneity (P < 0.001). HLA class I and II IMM landscapes were largely distinct suggesting a complementary role for class II IMMs in tumor rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell infiltration and programmed death-ligand 1 expression. Transcriptomic analyses revealed an inflamed tumor microenvironment for tumors harboring a high HLA class II IMM burden. CONCLUSIONS: HLA class II IMM burden identified patients with NSCLC and melanoma that attained longer survival after ICB treatment. Our findings suggest that HLA class II IMMs may impact responses to ICB in a manner that is distinct and complementary to HLA class I-mediated responses.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Melanoma , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , HLA Antigens , Histocompatibility Antigens Class I/genetics , Humans , Immune Checkpoint Inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mutation , Tumor MicroenvironmentABSTRACT
Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
