Neoadjuvant radiochemotherapy decreases the total amount of tumor infiltrating lymphocytes, but increases the number of CD8+/Granzyme B+ (GrzB) cytotoxic T-cells in rectal cancer

Abstract

Although neoadjuvant radiochemotherapy (nRCTx) is an established oncological treatment in patients with advanced rectal cancer, little is known about its effects on the tumor microenvironment. Quantity and composition of tumor infiltrating lymphocytes (TILs) are known to influence patients' prognosis but nRCTx-induced modifications are still unclear. We determined the composition of the immune cell infiltrate in rectal cancer after nRCTx and its influence on tumor regression, local recurrence rate and survival. We investigated density and composition of tumor infiltrating CD3 and CD8 T-cells and the quantity and ratio of CD8/GrzB T-cells to CD8 T-cells in 130 rectal cancers after nRCTx compared to a cohort of 30 primarily resected rectal cancers. Furthermore, we analyzed 22 pretherapeutic rectal cancer biopsies, later treated with nRCTx and surgery to evaluate nRCTx-induced modifications of the tumor microenvironment. The total numbers of CD3 and CD8 T-cells in tumor stroma (p < 0.001) and tumor epithelium (p < 0.001 CD3; 0.002 CD8) were significantly lower in rectal cancers after nRCTx compared to primarily resected cases, while the ratio of CD8/GrzB T-cells to CD8 T-cells was significantly increased in the nRCTx cohort (p < 0.001). In multivariate analyses, CD8/GrzB T-cells in the tumor stroma were significantly associated with high regression grade and a lower likelihood of local recurrence (p = 0.029). nRCTx modifies the tumor microenvironment of rectal cancer leading to a total decrease of TILs, but a relative increase in CD8/GrzB T-cells in the tumor stroma. CD8/GrzB T-cells may contribute to local tumor control and the better outcome.

Immune profile and immunosurveillance in treatment-naive and neoadjuvantly treated esophageal adenocarcinoma

“…Since the composition of the tumor microenvironment with immune cells and chemokines mainly drives efficacy of immunotherapy [24] and RCT profoundly suppresses the adaptive immune response, we propose that a combination of both could be restricted. Similar observations have been made in cervical and colorectal cancer patients [25,26].…”

“…Controversely, we could not observe any upregulation of PD-1 expression upon chemotherapy as described previously [25,26]. This might be due to the fact, that primary esophageal tumor samples show no differential expression of PD-1 and PD-L1 at all.…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…In this edition of the Trial Watch series, we discuss recent preclinical and clinical developments on ICD induction by anticancer chemotherapeutics in the context of immuno-oncology. Of note, other inducers of ICD including RT, 225,[340][341][342][343][344] oncolytic virotherapy, 345 high hydrostatic pressure, 12,15,346 photodynamic therapy and extracorporeal photochemotherapy 119,215,236,237,347 will not be discussed herein.…”

An integrated classifier improves prognostic accuracy in non-metastatic gastric cancer

“… 38 GZMB is secreted by CTLs and proteolytically processed to generate the active protease, which induces target cell apoptosis. 39 , 40 PAX5 plays an important role in B-cell differentiation. 41 , 42 Jiang et al have detected 27 immune features and constructed an immunoscore signature in 879 GC patients with AUC of 0.800 in the training cohort.…”