Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer

Cachot, Amélie; Bilous, Mariia; Liu, Yen‐Cheng; Li, Xiaokang; Saillard, Margaux; Cenerenti, Mara; Rockinger, Georg Alexander; Wyss, Tania; Guillaume, Philippe; Schmidt, Julien; Genolet, Raphaël; Ercolano, Giuseppe; Protti, Maria Pia; Reith, Walter; Ioannidou, Kalliopi; Leval, Laurence de; Trapani, Joseph A.; Coukos, George; Harari, Alexandre; Speiser, Daniel E.; Mathis, Alexander; Gfeller, David; Altug, Hatice; Romero, Pedro; Jandus, Camilla

doi:10.1126/sciadv.abe3348

Cited by 172 publications

(195 citation statements)

References 69 publications

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“…More recently, Cachot et al (51) confirmed the presence of cytolytic tumor-specific CD4 + T cells by mining single cell RNAseq datasets from melanoma patients. When validating these data, the authors demonstrated that these tumor-specific CD4 + T cells are able to kill tumor cells by a direct contact and granzymedependent mechanism, but with a delayed kinetic when compared to a more classical CTL.…”

Section: Discussionmentioning

confidence: 97%

Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients

et al. 2021

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Senescent T cells have been described during aging, chronic infections, and cancer; however, a comprehensive study of the phenotype, function, and transcriptional program of this T cell population in breast cancer (BC) patients is missing. Compared to healthy donors (HDs), BC patients exhibit an accumulation of KLRG-1+CD57+ CD4+ and CD8+ T cells in peripheral blood. These T cells infiltrate tumors and tumor-draining lymph nodes. KLRG-1+CD57+ CD4+ and CD8+ T cells from BC patients and HDs exhibit features of senescence, and despite their inhibitory receptor expression, they produce more effector cytokines and exhibit higher expression of Perforin, Granzyme B, and CD107a than non-senescent subsets. When compared to blood counterparts, tumor-infiltrating senescent CD4+ T cells show similar surface phenotype but reduced cytokine production. Transcriptional profiling of senescent CD4+ T cells from the peripheral blood of BC patients reveals enrichment in genes associated with NK or CD8+-mediated cytotoxicity, TCR-mediated stimulation, and cell exhaustion compared to non-senescent T cells. Comparison of the transcriptional profile of senescent CD4+ T cells from peripheral blood of BC patients with those of HDs highlighted marked similarities but also relevant differences. Senescent CD4+ T cells from BC patients show enrichment in T-cell signaling, processes involved in DNA replication, p53 pathways, oncogene-induced senescence, among others compared to their counterparts in HDs. High gene expression of CD4, KLRG-1, and B3GAT1 (CD57), which correlates with increased overall survival for BC patients, underscores the usefulness of the evaluation of the frequency of senescent CD4+ T cells as a biomarker in the follow-up of patients.

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Section: Discussionmentioning

confidence: 97%

Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients

et al. 2021

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“…Nonetheless, the details of how CD4 + GzmB + T cells located in the central tumor affects the anti-tumor immunity remains unclear and controversial, especially in pMMR CRC. Some argued that cytotoxic CD4 + T cells regulated the tumor rejection in a cytolytic molecules-dependent way (e.g., perforin, granzyme B) ( 69 ). Others believed that CD4 + GZMB + T cells mediated the recruitment of immune cells in melanoma through the release of inflammatory cytokines and chemokines, which would explain the increase infiltration of immune cells in the central tumor ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Immune Landscape Reveals Prognostic Significance of Cytotoxic CD4+ T Cells in the Central Region of pMMR CRC

Liu

Yan

et al. 2021

Front. Oncol.

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BackgroundMismatch repair proficient colorectal cancer (pMMR CRC) lacks effective treatments and has a poor prognosis, which can be attributed to the complexity of tumor microenvironment. The coordinated function of immune cells is vital to anti-tumor immunity. However, the spatial characteristics of immune cells in the pMMR CRC immune microenvironment and their relationship with clinical prognosis are not fully understood. Meanwhile, the immune modulatory effect of neoadjuvant chemotherapy (NCT), which is the first-line treatment of pMMR CRC, needs further investigation. Therefore, this study aims to explore the spatial dynamics of immune cells and its prognostic value in pMMR CRC.MethodsWe analyzed the various immune cells in formalin-fixed, paraffin-embedded tumor tissues which were collected from 77 patients with stage II/III of pMMR CRC, including 39 non-NCT treated and 38 NCT treated patients. We used the optimized multiplex immunohistochemistry (mIHC) to identify and quantify the density, type and location of immune cells in pMMR CRC. Multivariate survival analysis was performed to assess the relationship of immune profiles and clinical prognosis of pMMR CRC patients.ResultsThe densities of most T cell subsets, B cells and macrophages were higher in the central region of the pMMR CRC than in the invasion margin. Tumor infiltrating lymphocytes (TILs), especially the infiltration of CD4+ GzmB+ T cells in the central region of the tumor was identified to be positively correlated with the prognosis of the patients. Multivariate analysis confirmed that CD4+ GzmB+ T cells population was an independent predictor of disease-free survival (DFS) in non-NCT group. Meanwhile, NCT enhanced the infiltration of CD4+ GzmB+ T cells in the central region of the pMMR CRC, which was also identified as an independent protective factor of overall survival (OS) and DFS in NCT group.ConclusionWe demonstrated that the level of CD4+ GzmB+ T cells located in the center of tumor could provide great prognostic value for pMMR CRC patients. And the application of neoadjuvant chemotherapy further improves the infiltration of CD4+ GzmB+ T cells in the central compartment. Further studies into the application of CD4+ GzmB+ T cells in tumor immunotherapy are needed.

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“…Obesity impaired the ability of both CD4 + and CD8 + TILs to mount productive and sustained effector responses. While the anti-tumor activity of CD8 + T cells is well documented [ 47 ], emerging literature details essential anti-tumor activities of CD4 + T cells, including their ability to generate tumor-specific cytolytic responses and mediate the anti-tumor response through the production of cytokines [ 48 , 49 , 50 ]. The majority of publications detailing the impact of obesity on T cells have focused on the CD8 + subset [ 13 ], but here we are reporting an obesity-induced reduction in both CD4 + and CD8 + T cell effector responses.…”

Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing Mice

Turbitt

Boi

Gibson

et al. 2021

Cancers

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Associations between modifiable factors and the efficacy of cancer immunotherapies remain uncertain. We found previously that diet-induced obesity (DIO) reduces the efficacy of an immunotherapy consisting of adenovirus-encoded TRAIL plus CpG oligonucleotide (AdT/CpG) in mice with renal tumors. To eliminate confounding effects of diet and determine whether outcomes could be improved in DIO mice, we evaluated AdT/CpG combined with anti-CTLA-4 in diet-matched, obese-resistant (OB-RES) versus DIO tumor-bearing mice. Therapy-treated OB-RES mice displayed effective renal tumor control and sustained CD4+ and CD8+ T cell responses. In contrast, therapy-treated DIO mice exhibited progressive tumor outgrowth and blunted T cell responses, characterized by reduced intratumoral frequencies of IFNγ+ CD4+ and CD8+ T cells. Weak effector T cell responses in therapy-treated DIO mice were accompanied by low intratumoral concentrations of the T cell chemoattractant CCL5, heightened concentrations of pro-tumorigenic GM-CSF, and impaired proliferative capacity of CD44+CD8+ T cells in tumor-draining lymph nodes. Our findings demonstrate that in lean mice with renal tumors, combining in situ T cell priming upstream of anti-CTLA-4 enhances outcomes versus anti-CTLA-4 alone. However, host obesity is associated with heightened immunotherapy resistance, characterized by multi-factorial deficiencies in effector CD4+ and CD8+ T cell responses that extend beyond the tumor microenvironment.

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Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer

Cited by 172 publications

References 69 publications

Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients

Polyfunctional KLRG-1+CD57+ Senescent CD4+ T Cells Infiltrate Tumors and Are Expanded in Peripheral Blood From Breast Cancer Patients

Analysis of Immune Landscape Reveals Prognostic Significance of Cytotoxic CD4+ T Cells in the Central Region of pMMR CRC

Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing Mice

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