Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8+ T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.
Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX-bevacizumab), as compared with 20 healthy volunteers. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOLFOX-bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX-bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. Cancer Res; 76(18); 5241-52. ©2016 AACR.
Purpose/objective Radiotherapy (RT) induces an immunogenic antitumor response, but also some immunosuppressive barriers. It remains unclear how different fractionation protocols can modulate the immune microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors (ICI) in association with RT. However, only few trials aim to optimize the RT fractionation to improve efficacy of these associations. Here we sought to characterize the effect of different fractionation protocols on immune response with a view to associating them with ICI. Materials/methods Mice bearing subcutaneous CT26 colon tumors were irradiated using a SARRP device according to different radiation schemes with a same biologically effective dose. Mice were monitored for tumor growth. The radiation immune response (lymphoid, myeloid cells, lymphoid cytokines and immune checkpoint targets) was monitored by flow cytometry at different timepoints after treatment and by RNA sequencing analysis (RNAseq) . The same radiation protocols were performed with and without inhibitors of immune checkpoints modulated by RT. Results In the absence of ICI, we showed that 18x2Gy and 3x8Gy induced the longest tumor growth delay compared to 1×16.4Gy. While 3x8Gy and 1×16.4Gy induced a lymphoid response (CD8 + T-cells, Regulators T-cells), 18x2Gy induced a myeloid response (myeloid-derived suppressor cells, tumor-associated macrophages 2). The secretion of granzyme B by CD8 + T cells was increased to a greater extent with 3x8Gy. The expression of PD-L1 by tumor cells was moderately increased by RT, but most durably with 18x2Gy. T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression by CD8 + T-cells was increased with 3x8Gy, but decreased with 18x2Gy. These results were also observed with RNAseq. RT was dramatically more effective with 3x8Gy compared to all the other treatments schemes when associated with anti-TIGIT and anti-PD-L1 (9/10 mice in complete response). The association of anti-PD-L1 and RT was also effective in the 18x2Gy group (8/12 mice in complete response). Conclusion Each fractionation scheme induced different lymphoid and myeloid responses as well as various modulations of PD-L1 and TIGIT expression. Furthermore, 3x8Gy was the most effective protocol when associated with anti-PD-L1 and anti-TIGIT. This is the first study combining RT and anti-TIGIT with promising results; further studies are warranted. Electronic supplementary material The online version of this article (10.1186/s40425-019-0634-9) contains supplementary material, which is available to authorized users.
Sirtuin-1 deacetylates proteins and has emerged as a critical regulator of different cellular processes, particularly inflammation. Basal SIRT1 activity was previously found to limit Th9 and enhance Th17 differentiation in mice, but the effect of pharmacological SIRT1 activation on T cell differentiation and antitumor responses remains unclear. Here, we find that SIRT1 pharmacological agonists selectively impede mouse and human Th17 cell differentiation. SIRT1 activation induces STAT3 deacetylation, thus reducing its ability to translocate into the nucleus, bind to Rorc promoter, and induce its transcription. SIRT1 agonists reduce tumor growth in mice by blocking Th17 cell differentiation. In cancer patients, the SIRT1 agonist metformin reduced the frequency of Th17 cells and STAT3 acetylation levels. Altogether, these data underscore that SIRT1 activation impedes Th17 cell differentiation and thereby limits tumor growth and suggest that SIRT1 activators may directly target IL-17A functions.
Nivolumab, a monoclonal antibody targeting PD-1, is currently approved for metastatic non-small cell lung cancer (mNSCLC) treatment after failure of first-line chemotherapy. However, only a quarter of patients benefit from this therapy with objective clinical response. In this context, there is an unmet need for improved understanding of resistance mechanisms. Thus, we studied a prospective cohort of mNSCLC (n = 61) treated in second or third-line with nivolumab. We analyzed various blood myeloid and lymphoid markers by flow cytometry (176 variables) at baseline, and after 15 and 30 days of therapy. By attempting to link the evolution of peripheral lymphoid, myeloid cells and anti-PD-1 response, we observed that accumulation of lymphoid cells and monocytic MDSC (mMDSC) expressing, respectively, Tim-3 and galectin-9 is implicated in resistance to PD-1 blockade both for patients with primary or acquired secondary resistance to anti-PD-1. In vitro, anti-Tim-3 blocking antibody reverses resistance to anti-PD-1 in PBMC from lung cancer patients and high levels of blood mMDSC negatively impact on anti-PD-1 efficacy. Together, these data underline that the galectin-9/Tim-3 pathway and mMDSC are key mechanisms of primary or secondary resistance to anti-PD-1 and could be a new target for immunotherapy drug combinations.
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.
BackgroundT follicular helper cells (Tfh) are essential to shape B cell response during germinal center formation. Tfh accumulation has been reported in various human cancers, with positive or negative prognostic roles. However, the mechanisms explaining the accumulation of Tfh and their role in cancer remain obscure.MethodsIn vitro differentiated and mouse cell sorted Tfh phenotype was evaluated by flow cytometry and quantitative PCR (qPCR). Antitumor effect of Tfh was evaluated by adoptive transfer in different tumor-bearing mice models. The involvement of immune cells, cytokines and chemokines was evaluated, using depleting antibodies. Chemokines and cytokines expression and production were evaluated by qPCR and ELISA. In human, the impact of immune cells and chemokines on survival was evaluated by analyzing transcriptomic data from public databases and from our own patient cohorts.ResultsIn this study, we show that Tfh exert an antitumor immune effect in a CD8+-dependent manner. Tfh produce interleukin-21, which sustains proliferation, viability, cytokine production and cytotoxic functions of exhausted T cells. The presence of Tfh is required for efficacy of antiprogrammed cell death ligand-1 therapy. Tfh accumulate in the tumor bed and draining lymph nodes in different mouse cancer models. This recruitment is due to the capacity of transforming growth factor β to drive Chemokine (C-X-C motif) Ligand 13 expression, a chemoattractant of Tfh, by intratumor CD8+ T cells. Accumulation of Tfh and exhausted CD8+ T cells predicts cancer outcome in various cancer types. In patients treated with anti-programmed cell death-1 mAb, accumulation of Tfh and CD8+ at the tumor site is associated with outcome.ConclusionThis study provides evidence that CD8+/Tfh crosstalk is important in shaping antitumor immune response generated by immunotherapy.
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