Somatic Mutations and Immune Alternation in Rectal Cancer Following Neoadjuvant Chemoradiotherapy

Abstract

Checkpoint blockade therapy triggers tumor-specific immune responses in a variety of cancer types. We presumed that rectal cancer patients could have become sensitive to immunotherapy after receiving neoadjuvant chemoradiotherapy (nCRT). In this study, we report immune alternation in post-nCRT patients compared with pretreatment conditions from gene-expression omnibus (GEO) data. Whole-exome sequencing of 14 locally advanced rectal cancer (LARC) patient samples showed that nCRT induced new mutations compared with the paired pretreatment biopsies, evidenced by appearance of a neoantigen landscape. An association was identified between mutation burden and enrichment of immune activation-related pathways. Animal experiment results further demonstrated that radiotherapy enhanced the efficacy of anti-PD-1. Mutation burden and the neoantigens of LARC patients were associated with response to nCRT. The mRNA expression profiling of 66 pretreatment biopsy samples from LARC patients showed that immune activation-related pathways were enriched in response to nCRT. PD-L1 expression was negatively correlated with disease-free survival in the CD8low expression patient group who received nCRT in a cohort of 296 samples. Thus, nCRT was able to alter immune function in LARC patients, which may be associated with the appearance of neoantigens. Neoantigens could make rectal cancer patients potential candidates to receive checkpoint blockade immunotherapy, and mutation burden could be a useful biomarker to stratify patients into responding and nonresponding groups for immunotherapy.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…In addition to the above-mentioned proposed strategies to enhance efficacy, we must also discuss chemoradiotherapy combined with anti-PD1 immunotherapy, which has been implemented in clinical practice. Clinical trials have shown that this strategy have achieved satisfactory results in NSCLC, gastric, (triple-negative) breast, recurrent nasopharyngeal, and rectal cancers, hematological malignancies, and other tumors [171][172][173][174][175][176][177][178]. The combined effects of chemoradiotherapy are due to the enhanced immunogenicity of tumor cells, antigen presentation, and recognition of tumor cells by T cells.…”

Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer

“…Our previous work demonstrated that RT combined with anti-PD1 enhanced the control of tumor growth in a single dose radiotherapy mice model. 52 Dovedi et al ’s work showed that the combination of fractionated radiotherapy and anti-PD1 generated systemic antitumor responses and tumor control in both irradiated tumor and abscopal effect. 44 In our future study, we plan to investigate the effect of combination of anti-PD1 and RT on rectal cancer metastasis, and compare the effects of RT combined with CTLA4 and PD1.…”

Tumour budding and CD8+ T cells: ‘attackers’ and ‘defenders’ in rectal cancer with and without neoadjuvant chemoradiotherapy

“…This result seems to conflict with previous reports suggesting that CD8 + T cells are increased after radiochemotherapy, and confer an improved overall and disease‐free survival. It is suggested that immune activation following neoadjuvant therapy is related to neoantigens arising from the tumour mutation burden (TMB) 19 . Ji et al .…”