Abstract
Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum–tumor axis, influencing clinical outcome.
Highlights
The field of cancer treatment has seen major advancements over the last few years with the approval of immune checkpoint inhibitors (ICI) for multiple indications
We showed that T follicular helper (Tfh) primed in the mesenteric lymph nodes (mLN) post OXA accumulates in colonic tumor beds instead of being redirected toward the chemotherapy-inflamed ileum
Immunofluorescence-based staining of T-cell subsets in the ilea and tumor beds revealed an inverse correlation between CD3+ and CD4+ T lymphocytes within the ileal epithelium (EP) or lamina propria (LP), and CD8+ tumorinfiltrating lymphocytes (TILs) in the invasive margins of the resected proximal colon cancer (pCC) (Fig. 1A, B)
Summary
The field of cancer treatment has seen major advancements over the last few years with the approval of immune checkpoint inhibitors (ICI) for multiple indications. ICIs do not benefit all patients; there are still major challenges to overcome primary or secondary resistance against immunotherapy. For colorectal cancer (CRC), These authors contributed : Marion Picard, Satoru Yonekura. These authors jointly supervised this work: Laurence Zitvogel, Maria Paula Roberti. Extended author information available on the last page of the article microsatellite stability (MSS) is resistant to ICI and represents the vast majority of CRC [1]. Combination chemotherapy based on the use of 5-fluorouracil (5-FU) plus oxaliplatin (OXA) (FOLFOX) is routinely used as first-line treatment for advanced CRC [2], with no curative intention. The identification of new therapeutic options and associated biomarkers will help selecting patients for clinical trials and evaluating therapeutic responses
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