Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo, the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloidderived suppressor cells but eliminated type-2 tumorassociated macrophages (TAM2), resulting in higher cyto-toxic CD8 þ T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8 þ T cells, leading to secondary T-cell exhaustion. Finally, although anti-PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti-PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.
Low-grade serous carcinoma represents a minority of serous carcinoma. Although they have better prognosis than high-grade serous carcinoma, they respond poorly to chemotherapy. Thus, it appears necessary to find other treatments such as targeted therapies. Since RAS or RAF mutations occur frequently in low-grade serous carcinoma and lead to constitutively activated MAPK cascade, MEK inhibition should be effective in the treatment of low-grade serous carcinoma. So, we wanted to evaluate the clinical benefit of MEK inhibitors in the management of advanced-stage low-grade serous carcinoma harboring KRAS or NRAS mutation. We report a case series of three women with advanced-stage low-grade serous carcinoma harboring RAS mutation who had stabilization of their disease during several months under targeted therapy combining anti-EGFR antibody and MEK inhibitor. We performed in vitro experiments, confirming the effectiveness of MEK inhibitor on the KRAS-mutated OVCAR-5 cell line, and the constitutively activation of MAPK cascade in RAS-mutated carcinoma. However, it seems that the anti-EGFR antibody does not provide any additional benefit. After whole exome analysis is carried out on the patient with the shortest response, we observed the appearance of RB1 loss-of-function mutation that could be a mechanism of resistance to MEK inhibitors in RAS- of RAF-mutated cancers. The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance. RB1 loss could be a mechanism of resistance to MEK inhibitors in RAS-mutated low-grade serous carcinoma.
<div>Abstract<p>Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) <i>in vitro</i> in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. <i>In vivo</i>, the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloid-derived suppressor cells but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8<sup>+</sup> T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8<sup>+</sup> T cells, leading to secondary T-cell exhaustion. Finally, although anti–PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti–PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD <i>in vivo,</i> providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.</p></div>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.