The Adaptive Immune Landscape of the Colorectal Adenoma-Carcinoma Sequence.

João Augusto Freitas,Lídia Pinho,Joana Reis,Cecília Durães,Dina Leitão,Louisa Spaans,Fátima Carneiro,Irene Gullo,Sara Miranda,José Luis Costa,Carlos Resende,Manuela Baptista,José Carlos Machado,Diogo Garcia,Fabiana Sousa

doi:10.3390/ijms22189791

Abstract

Background. The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). Methods. We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). Results. The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. Conclusions. The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.

Highlights

To assess whether the tumor immune microenvironment could vary depending on the hereditary or sporadic background of the neoplastic lesions, we investigated the immune landscape between the two cohorts for low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive ADC lesions (Figure 3)
Supporting the most recent findings in the literature [17], our findings suggest that colorectal carcinogenesis is characterized by the gradual loss of adaptive immune cell counts along the colorectal adenoma–carcinoma sequence (ACS), in both sporadic and hereditary lesions
Our findings suggest that the colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment

Summary

Introduction

The etiopathogenesis of most colorectal carcinomas (CRC) follows the conventional adenoma–carcinoma sequence (ACS), in which colorectal adenomas with low-grade dysplasia (LGD) and/or high-grade dysplasia (HGD) evolve to invasive adenocarcinoma (ADC), through a stepwise accumulation of genetic and epigenetic alterations. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression

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Discussion

Conclusion