INFLUENCE OF HLA CLASS I AND TUMOR NEOANTIGENS IN TREATMENT RESPONSE WITH BCG (BACILLUS CALMETTE-GUÉRIN) IMMUNOTHERAPY IN NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

Around 70-80% of bladder cancer cases correspond to non-invasive forms (NMIBC). NMIBC treatment is surgical, followed by adjuvant immunotherapy with intra-vesical applications of BCG vaccine in cases with a high or intermediate risk of disease recurrence. It is hypothesized that BCG immunotherapy stimulates the patient’s immune response, which in turn activate lymphocytes supposed to recognize tumor neoantigens and eliminate cancer cells. About 3040% of patients do not respond to BCG treatment and relapse, also 10-25% progress to invasive forms (MIBC), and to date, there are no predictive biomarkers of BCG response in the clinical practice. MIBC cases previously treated with BCG are enriched for mutations in HLA Class I genes, evidence that NMIBC severity is related to the specificity of the antigen presentation mechanism. Surprisingly, NMIBC data correlating the response to BCG and tumor mutation burden is controversial in the literature. For distinct tumor types, recent works have demonstrated that neoantigens with higher homology to infectious disease-related molecules are biomarkers of better clinical outcomes; however, this analysis has not yet been adopted to explain progression and response to treatment in NMIBC. We hypothesize that (i) the number of neoantigens similar to microbial epitopes is predictive of response to BCG and (ii) somatic and polymorphic HLA variants modulate peptide molecular affinity, interfering in neoantigens recognition and immune response. We HLA-typed and quantified neoantigens from exomes of 35 primary tumors of BCG treated patients (17 sensitive and 18 resistant) using bioinformatics tools. Excluding synonymous, we observed that not all mutations are immunogenic: on average 59.46% are neoantigens (40.4-94.3% per patient). There is a significant correlation between total tumor mutations and amount of predicted neoantigens (Pearson correlation, p-val < 2x10e-16). Moreover, sensitive tumors have more neoantigens compared to resistant ones (Wilcoxon test, p-val = 0.03), evidencing a significant association between quantity of neoantigens and greater relapse-free survival (Log-rank test, p-val = 0.017), a fact not yet demonstrated for NMIBC. We are currently employing a mathematical model to estimate the degree of similarity between tumor peptides and pathogen epitopes. Finally, we did not observe a significant correlation between BCG response and loss of diversity in tumor HLA-A, B, or C (Log-rank test, p-val = 0.52).

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
23 October 2019