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TGF-β1, β2 and β3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-β inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-β1 production by Tregs with antibodies against GARP:TGF-β1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-β1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8 + T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-β1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-β1 mAbs, by selectively blocking a single TGF-β isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer. Inhibiting TGF-β1 to increase immune responses against tumors bears the risk of tumor-promoting toxicity. Here the authors show that selectively blocking TGF-β1 produced by immunosuppressive cells is feasible with anti-GARP:TGF-β1 antibodies and improves the efficacy of PD-1 blockade immunotherapy.

Ketorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival. The KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival. Between February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years. At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65-2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34-3.51). A single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed. ClinicalTrials.gov NCT01806259.

Background Inflammation is associated with a worse outcome in cancer and neutrophil:lymphocyte ratio (NLR) is a strong prognostic value. In cancer, nonsteroidal anti-inflammatory drugs (NSAIDs) could be of interest. We investigated the prognostic significance of NLR and the impact of intraoperative NSAIDs in cancer surgeries. Methods We performed an observational study in early breast, kidney, and lung cancers (357, 227, and 255 patients) with uni- and multivariate analyses (Cox model). Results In breast cancer (Centre 1), NLR ≥ 4 is associated with a higher risk of relapse (hazards ratio (HR) = 2.41; 95 % confidence interval (CI) 1.01–5.76; P  = 0.048). In breast cancer (Centre 2), NLR ≥ 3 is associated with a higher risk of relapse (HR = 4.6; 95 % CI 1.09–19.1; P  = 0.04) and higher mortality (HR = 4.0; 95 % CI 1.12–14.3; P  = 0.03). In kidney cancer, NLR ≥ 5 is associated with a higher risk of relapse (HR = 1.63; 95 % CI 1.00–2.66; P  = 0.05) and higher mortality (HR = 1.67; 95 % CI 1.0–2.81; P  = 0.05). In lung cancer, NLR ≥ 5 is associated with higher mortality (HR = 1.45; 95 % CI 1.02–2.06; P  = 0.04). The intraoperative use of NSAIDs in breast cancer patients (Centre 1) is associated with a reduced recurrence rate (HR = 0.17; 95 % CI 0.04–0.43; P  = 0.0002) and a lower mortality (HR = 0.25; 95 % CI 1.08–0.75; P  = 0.01). NSAIDs use at the beginning of the surgery is independently associated with a lower metastases risk after lung cancer surgery (HR = 0.16; 95 % CI 0.04–0.63; P  = 0.009). Ketorolac use is independently associated with longer survival (HR = 0.55; 95 % CI 0.31–0.95; P  = 0.03). Conclusions In these cohorts, these analyses show that NLR is a strong perioperative prognosis factor for breast, lung, and kidney cancers. In this context, intraoperative NSAIDs administration could be associated with a better outcome.

GARP is a transmembrane protein present on stimulated human regulatory T lymphocytes (Tregs), but not on other T lymphocytes (Th cells). It presents the latent form of TGF-β1 on the Treg surface. We report here that GARP favors the cleavage of the pro-TGF-β1 precursor and increases the amount of secreted latent TGF-β1. Stimulated Tregs, which naturally express GARP, and Th cells transfected with GARP secrete a previously unknown form of latent TGF-β1 that is disulfide-linked to GARP. These GARP/TGF-β1 complexes are possibly shed from the T cell surface. Secretion of GARP/TGF-β1 complexes was not observed with transfected 293 cells and may thus be restricted to the T cell lineage. We conclude that in stimulated human Tregs, GARP not only displays latent TGF-β1 at the cell surface, but also increases its secretion by forming soluble disulfide-linked complexes. Moreover, we identified six microRNAs (miRNAs) that are expressed at lower levels in Treg than in Th clones and that target a short region of the GARP 3' UTR. In transfected Th cells, the presence of this region decreased GARP levels, cleavage of pro-TGF-β1, and secretion of latent TGF-β1.

In this Timeline, the authors discuss the identification of tumour antigens that are recognized by T lymphocytes and how these findings can be effectively and safely transferred to the clinic. In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.

Four leading tumour immunologists provide their opinions on the determinants of immunogenicity and how we might therapeutically improve tumour immunogenicity in the future. Many standard and targeted therapies, as well as radiotherapy, have been shown to induce an anti-tumour immune response, and immunotherapies rely on modulating the host immune system to induce an anti-tumour immune response. However, the immune response to such therapies is often reliant on the immunogenicity of a tumour. Tumour immunogenicity varies greatly between cancers of the same type in different individuals and between different types of cancer. So, what do we know about tumour immunogenicity and how might we therapeutically improve tumour immunogenicity? We asked four leading cancer immunologists around the world for their opinions on this important issue.

Background Combining immune checkpoint inhibitors (ICI) with neoadjuvant chemotherapy (NACT) has been the standard of care for stage II and III triple negative breast cancer (TNBC) since 2021. For Luminal B/HER2(-) breast cancers (BC) recent results from randomized phase 3 clinical trials demonstrated an improvement in pathological complete response (pCR) when ICI are combined with overall NACT. Emerging real-life data on TNBC reveal rates of ICI-related toxicities higher than expected, raising questions about the possibility of reducing ICI exposure during NACT while maintaining an efficacy advantage. The B-IMMUNE study explored the safety and efficacy of short-course durvalumab combined with EC during NACT in locally advanced BC. Patients and methods The prospective phase 1b/2 trial included patients with locally advanced Luminal B/HER2(-) or TNBC who were treated with paclitaxel 80mg/m2 weekly from weeks 1–12, followed by 4 cycles of dose-dense epirubicin 90mg/m2 and cyclophosphamide 600mg/m2 biweekly (ECdd), in a neoadjuvant setting. Phase 1b evaluated a single infusion of durvalumab 1500mg combined with the 3rd cycle of ECdd and phase 2 evaluated two infusions with the 1st and 3rd cycles of ECdd respectively. The primary endpoints were safety and pathological complete response (pCR) rate versus historical control. Based on Simon’s two-stage design, the trial was considered positive if > 8/20 pCRs were observed among TNBC patients and > 5/22 for luminal B HER2(-) BC patients. Results Fifty patients were considered for safety analyses and 34% of them experienced grade 3–4 adverse events (AEs) and 8% immunity-related AEs. Of the 47 patients treated with durvalumab in phase 2, 46 (22 TNBC and 24 Luminal B/HER2(-) BC) were considered for efficacy analyses. A pCR was observed in 12/22 TNBC patients (55%) and 8/24 Luminal B/HER2(-) BC patients (33%). Conclusions The B-IMMUNE study achieved its primary objective by showing that the addition of only 2 doses of durvalumab to NACT seems to improve the pCR rate compared to a historical control without ICI, for both TNBC and Luminal B/HER2(-) BC, while maintaining an acceptable safety profile. De-escalation of ICI in the neoadjuvant setting should be further investigated in phase 3 trials. Trial registration EudraCT: 2016–003998-1 date: 19 January 2017.

When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP + blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.

Bladder carcinomas are immunogenic, and patients with bladder cancer benefit from immune checkpoint therapy. This is correlated to a high tumor mutation burden, which provides a higher number of neoepitopes that can be recognized by tumor-specific CD8 T cells. Intravesical Bacillus Calmette-Guérin (BCG) is used to treat non-muscle invasive bladder cancer (NMIBC), but its mechanism of action remains elusive. Most lymphocytes appearing in the urine of BCG-treated patients are CD4 T cells though preclinical studies showed that CD8 T cells are also necessary for BCG treatment efficacy. It is currently unknown which proportion of patients with non-metastatic bladder cancer develop a spontaneous antitumor CD8 response, and if BCG treatment influences this response. In a first cohort of 15 NMIBC and 9 muscle invasive bladder cancer patients, we used IFN- ELISPOT assays to screen for the presence of anti-neoepitope CD8 T cells in the blood, tumor and urine. In a second cohort of 4 NMIBC patients, we analyzed the features and specificity of CD8 T cells infiltrating the tumoral or bladder tissues before and after BCG using single cell transcriptomic analyses. A total of 31 tumor-infiltrating CD8 clonotypes were screened against neoepitopes and tumor cDNA libraries. 9 out of 24 patients from the first cohort mounted a spontaneous and functional anti-neoepitope T-cell response in blood and/or tumor. In 5 patients from this cohort who were treated with BCG, no neoantigen-specific T cells were detected in urine during treatment. In the second cohort, 6 out of 6 TCRs from exhausted CD8 TILs from one patient recognized 5 different neoepitopes. T-cell receptor (TCR) repertoire analyses indicated that the frequencies of these tumor-specific T cells did not increase after BCG instillations, neither in the bladder nor in the blood. None of the 25 other TCRs of CD8 T cells recognized tumor-specific antigens. We show that one third of patients with non-metastatic bladder cancer mount a spontaneous and functional anti-neoepitope CD8 T-cell response detectable in blood or tumor. In 4 patients with NMIBC, BCG treatment did not boost or induce the anti-neoepitope response, suggesting alternative mechanisms of action for its efficacy.

Human regulatory T cells (Tregs) suppress other T cells by converting the latent, inactive form of TGF-β1 into active TGF-β1. In Tregs, TGF-β1 activation requires GARP, a transmembrane protein that binds and presents latent TGF-β1 on the surface of Tregs stimulated through their T cell receptor. However, GARP is not sufficient because transduction of GARP in non-Treg T cells does not induce active TGF-β1 production. RGD-binding integrins were shown to activate TGF-β1 in several non-T cell types. Here we show that αVβ8 dimers are present on stimulated human Tregs but not in other T cells, and that antibodies against αV or β8 subunits block TGF-β1 activation in vitro. We also show that αV and β8 interact with GARP/latent TGF-β1 complexes in human Tregs. Finally, a blocking antibody against β8 inhibited immunosuppression by human Tregs in a model of xenogeneic graft-vs.-host disease induced by the transfer of human T cells in immunodeficient mice. These results show that TGF-β1 activation on the surface of human Tregs implies an interaction between the integrin αVβ8 and GARP/latent TGF-β1 complexes. Immunosuppression by human Tregs can be inhibited by antibodies against GARP or against the integrin β8 subunit. Such antibodies may prove beneficial against cancer or chronic infections.