Activin-A Impedes the Establishment of CD4+ T Cell Exhaustion and Enhances Anti-Tumor Immunity in the Lung

Abstract Background: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer.Methods: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients.Results: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells.Conclusions: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

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Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02092-5 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Ioannis Morianos ◽

Aikaterini Tsitsopoulou ◽

Konstantinos Potaris ◽

Dimitrios Valakos ◽

Ourania Fari ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

T Cell ◽

Cancer Patients ◽

Tumor Immunity ◽

Lung Tumor ◽

Activin A ◽

Type I ◽

Lung Cancer Patients ◽

Tumor Bearing

Abstract Background Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. Methods To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4−/−-tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Results Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4−/− recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. Conclusions In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

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Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation

The Journal of Immunology ◽

10.4049/jimmunol.168.9.4272 ◽

2002 ◽

Vol 168 (9) ◽

pp. 4272-4276 ◽

Cited By ~ 479

Author(s):

Edward Y. Woo ◽

Heidi Yeh ◽

Christina S. Chu ◽

Katia Schlienger ◽

Richard G. Carroll ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cancer Patients ◽

Cutting Edge ◽

T Cell Proliferation ◽

Lung Cancer Patients

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Highly differentiated CD4 T cells Unequivocally Identify Primary Resistance and Risk of Hyperprogression to PD-L1/PD-1 Immune Checkpoint Blockade in Lung Cancer

10.1101/320176 ◽

2018 ◽

Cited By ~ 7

Author(s):

Miren Zuazo-Ibarra ◽

Hugo Arasanz ◽

Gonzalo Fernández-Hinojal ◽

Gato-Cañas María ◽

Berta Hernández-Marín ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

T Cell ◽

Cancer Patients ◽

Cd4 T Cells ◽

Critical Issue ◽

Immune Checkpoint Blockade ◽

Cd4 T Cell ◽

Primary Resistance ◽

Lung Cancer Patients

AbstractThe majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This therapy may even accelerate progression and death in a group of patients called hyperprogressors. Here we demonstrate that the efficacy of PD-L1/PD-1 blockade therapy relies on baseline circulating highly-differentiated CD28− CD27− CD4 T cells (THD cells), which segregate patients in two non-overlapping groups. THD cells in cancer patients mostly comprised of central memory subsets that potently co-upregulated PD-1 and LAG3 upon antigen recognition. Low baseline THD numbers unequivocally identified intrinsic non-responders and hyperprogressors, whom aberrantly responded to therapy with a potent systemic proliferative THD cell burst. Responder patients showed significant reductions in systemic CD4 THD cells throughout therapy linked to expansion of the CD28+ CD27+ CD4 T cell compartment. Quantification of THD cells from peripheral blood samples prior to therapy allows identification of non-responders, hyperprogressors and responders, a critical issue in clinical oncology. These results place CD4 T cell responses at the center of anti-tumor immunity.

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TNF Receptor Type II Is Critical to the Expansion and Suppressive Function of Regulatory T Cells in Malignant Pleural Effusion from Lung Cancer Patients

SSRN Electronic Journal ◽

10.2139/ssrn.3471323 ◽

2019 ◽

Author(s):

Lin-Lin Ye ◽

Wen-Bei Peng ◽

Yi-Ran Niu ◽

Xiao-Shan Wei ◽

Zi-Hao Wang ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Pleural Effusion ◽

Regulatory T Cells ◽

Cancer Patients ◽

Malignant Pleural Effusion ◽

Receptor Type ◽

Type Ii ◽

Tnf Receptor ◽

Lung Cancer Patients

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183 Overcoming immunotherapy resistance in T cell-inflamed lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0183 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A197-A197

Author(s):

Brendan Horton ◽

Duncan Morgan ◽

Noor Momin ◽

Vidit Bhandarkar ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

T Cell ◽

Cell Line ◽

Cancer Patients ◽

Rna Sequencing ◽

Mechanistic Study ◽

Nsclc Cell Line ◽

Effector Molecule ◽

Effector Molecules

BackgroundTumor infiltrating T cells (TIL) are highly correlated with response to checkpoint blockade immunotherapy (CBT) in melanoma. However, in non-small cell lung cancer (NSCLC), 61% of patients have TIL, but only 32% respond to CBT. It is unknown how these T cell-inflamed tumors are resistant to CBT. Understanding and overcoming this resistance would greatly increase the number of cancer patients who benefit from CBT.MethodsTo understand lung-specific anti-tumor immune responses, a NSCLC cell line derived from an autochthonous murine lung cancer (KP cell line) was transplanted into syngeneic C57BL/6 mice subcutaneously or intravenously. To study antigen-specific responses, the KP cell line was engineered with SIY and 2C TCR transgenic T cells, which are specific for SIY, were adoptively transferred into tumor-bearing animals.ResultsSubcutaneous KP tumors responded to CBT (aCTLA-4 and aPD-L1) with significant tumor regression while lung KP tumors were CBT resistant. Immunohistochemistry found that this was not due to lack of T cell infiltration, as lung tumors contained 10-fold higher numbers of CD8+ TIL than subcutaneous tumors. Single cell RNA sequencing of TIL uncovered that CD8+ TIL in lung lesions had blunted effector molecule expression that correlated with a lack of IL-2 signaling. Adoptive transfer of naïve, tumor-reactive 2C T cells resulted in equally robust T cell proliferation in both the inguinal and mediastinal lymph nodes (LNs). However, RNA sequencing of adoptively transferred 2C T cells isolated 3-days after transfer from draining LNs identified that T cells activated in the mediastinal LN had reduced levels of IL-2 signaling and blunted effector functions early during priming. Flow cytometry confirmed that T cells primed in the mediastinal LNs did not express CD25, GZMB, or IFN-g, while T cells in inguinal LNs upregulated all three of these effector molecules. Delivery of IL-2 and IL-12 during priming was sufficient to restore effector molecule expression on 2C T cells in mediastinal LNs. Analysis of published patient data identified that a subset of lung cancer patients showed a sizable population of CD8+ TIL with low IL-2 signaling and low expression of effector molecules, including common targets of CBT.ConclusionsImmunotherapy resistance in T cell-inflamed tumors is due to defective CD8+ T cell effector differentiation. IL-2-based therapies could enhance differentiation of functional CD8+ effector T cells and could turn immunotherapy resistant tumors to immunotherapy sensitive tumors. This is the first mechanistic study providing evidence for a distinct type of T cell dysfunction resistant to current CBT.Ethics ApprovalThis study was approved by MIT’s Committee on Animal Care, protocol number 0220-006-23.

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