Dados do Resumo

Título

Are immunotherapy biomarkers good predictors of response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer?

Introdução

The standard initial treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT), to reduce tumor size for subsequent total mesorectal excision. After nCRT, a significant proportion of patients (10-30%) achieve a complete pathological response (pCR) and may be eligible for organ-preserving approaches. However, current clinical, radiological, and molecular tools cannot reliably predict pCR or distinguish between responders (nCRT-R) and non-responders (nCRT-NR). Therefore, identifying predictive biomarkers for nCRT response could greatly influence the clinical management of LARC patients. Research consistently shows that in various cancers and treatment protocols, the presence of tumor-infiltrating lymphocytes (TILs), particularly those enriched with cytotoxic CD8+ T-cells, correlates with improved prognosis and treatment outcomes. A recent study revealed that some LARC tumors exhibit "hot" immune microenvironments, which were somewhat linked to enhanced nCRT responses. Moreover, an immunohistochemistry-based score assessing CD3+ and CD8+ T-cell enrichment in LARC TILs is being considered as a potential preoperative predictive test.

Objetivo

This work objective is to evaluate if the elements of the anti-tumor immune response, such as the antigen-presentation process, are promising sources of molecular biomarkers.

Métodos

We performed exome and T-cell receptor (TCR) sequencing on 69 LARC tumors (15 nCRT-R and 37 nCRT-NR) to examine whether HLA, neoantigens, and TCR genetic diversity were associated with nCRT response.

Resultados

The neoantigen load (NAL), a measure of tumor immunogenicity, was higher in nCRT-NR patients (Wilcoxon test, p=0.03). HLA somatic mutations did not significantly affect antigen presentation or drug resistance, as only 8 mutations were identified in 8 patients (6 nCRT-NR vs. 2 nCRT-R, Pearson’s Chi-squared, p=0.76). Additionally, HLA polymorphism was not significant, with no notable enrichment for any HLA allele or loss of heterozygosity in nCRT response groups (Pearson’s Chi-squared, p=0.64). Also, no association was observed between response to nCRT and TCR Shannon diversity (Wilcoxon test, p=0.25). We did not observe any difference in the gene composition of TCR sequences of responders and no responders, though we were unable to quantify specifically the repertoire of anti-tumor CD8+ T-cells. Lastly, we observed that the interactions between HLA-neoantigen-TCR are more prone to happen for nCRT-R patients (Wilcoxon test, p<0.001).

Conclusões

These findings suggest that immunogenetic biomarkers do not predict nCRT response and that nCRT-NR tumors may represent a heterogeneous group, including highly immunogenic LARC cases (with high NAL), which could potentially benefit from immunotherapy.

Financiador do resumo

FAPESP 2018/15582-9

Palavras Chave

Molecular Biomarkers; Neoadjuvant Chemoradiotherapy; Locally advanced rectal cancer