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Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8 + cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization., Competing Interests: Declaration of interests G.C. has received grants, research support, or has been coinvestigator in clinical trials by Bristol-Myers Squibb, Tigen Pharma, Iovance, F. Hoffmann-La Roche AG, and Boehringer Ingelheim. The Lausanne University Hospital (CHUV) has received honoraria for advisory services G.C. has provided to Genentech, AstraZeneca AG, and EVIR. G.C. has previously received royalties from the University of Pennsylvania for CAR-T cell therapy licensed to Novartis and Tmunity Therapeutics. D.D.L., S.B., A.H., and G.C. are inventors on patent applications filed by the Ludwig Institute for Cancer Research Ltd. on behalf of the University of Lausanne and the CHUV pertaining to the subject matter disclosed herein, and such patent applications have been licensed to Tigen Pharma SA. S.Z. is currently an employee of F. Hoffmann-La Roche. O.M. has consulting/advisory roles for Bristol Myers Squibb, MSD, Roche, Novartis, Amgen, Pierre Fabre, and Neracare; research grants from Bristol Myers Squibb, MSD, Amgen, and PCL; was a consultant advisor or paid speaker for Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Amgen, and Nektar; and has received research funding from Bristol Myers Squibb and Pierre Fabre and is the cofounder of a cell therapy company called Cellula., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A central challenge in developing personalized cancer cell immunotherapy is the identification of tumor-reactive T cell receptors (TCRs). By exploiting the distinct transcriptomic profile of tumor-reactive T cells relative to bystander cells, we build and benchmark TRTpred, an antigen-agnostic in silico predictor of tumor-reactive TCRs. We integrate TRTpred with an avidity predictor to derive a combinatorial algorithm of clinically relevant TCRs for personalized T cell therapy and benchmark it in patient-derived xenografts., (© 2024. The Author(s).)

Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell-intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 + TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor-reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Air pollution in subway environments is a growing concern as it often exceeds WHO recommendations for indoor air quality. Ultrafine particles (UFP), for which there is still no regulation nor a standardized exposure monitoring method, are the strongest contributor to this pollution when the number concentration is used as exposure metric., Objectives: We aimed to assess the real-time UFP number concentration in the personal breathing zone (PBZ) of three types of underground Parisian subway professionals and analyze it using a novel Bayesian spline approach. Consecutively, we investigated the effect of job, week day, subway station, worker location, and some further events on UFP number concentrations., Methods: The data collection procedure originated from a longitudinal study and lasted for a total duration of 6 weeks (from October 7 to November 15, 2019, i.e. two weeks per type of subway professionals). Time-series were built from the real-time particle number concentration (PNC) measured in the PBZ of professionals during their work-shifts. Complementarily, contextual information expressed as Station, Environment, and Event variables were extracted from activity logbooks completed for every work-shift. A Bayesian spline approach was applied to model the PNC within a Bayesian framework as a function of the mentioned contextual information., Results: Overall, the Bayesian spline method suited a real-time personal PNC data modeling approach. The model enabled estimating the differences in UFP exposure between subway professionals, stations, and various locations. Our results suggest a higher PNC closer to the subway tracks, with the highest PNC on subway station platforms. Studied event and week day variables had a lesser influence., Conclusion: It was shown that the Bayesian spline method is suitable to investigate individual exposure to UFP in underground subway settings. This method is informative for better documenting the magnitude and variability of UFP exposure, and for understanding the determinants in view of further regulation and control of this exposure., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)