Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

  title={Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade},
  author={Douglas C. Palmer and Beau R. Webber and Yogin Patel and Matthew J. Johnson and Christine M. Kariya and Walker S. Lahr and Maria R Parkhurst and Jared J. Gartner and Todd D Prickett and Frank J. Lowery and Rigel J. Kishton and Devikala Gurusamy and Zulmarie Franco and Suman Kumar Vodnala and Miechaleen D. Diers and Natalie K. Wolf and Nicholas J. Slipek and David H. McKenna and Darin Sumstad and Lydia Viney and Tom Henley and Tilmann B{\"u}rckst{\"u}mmer and Oliver Baker and Ying Hu and Chunhua Yan and Daoud M. Meerzaman and Kartika Padhan and Branden S. Moriarity and Winifred M. Lo and Parisa Malekzadeh and Li Jia and Drew C. Deniger and Shashank J. Patel and Paul F. Robbins and R Scott McIvor and Modassir Choudhry and Nicholas P. Restifo and Steven A. Rosenberg},
While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen-expressing tumors, their adoptive transfer fails to consistently elicit durable tumor regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX in TIL senescence. We found these markers were inversely expressed to Cytokine-Induced SH2 protein (CISH), a negative regulator of TCR signaling and tumor immunity in mice. To evaluate the physiological role of… 

Genetic editing of CISH enhances T cell effector programs independently of immune checkpoint cell surface ligand expression

Comparing the function of CISH deletion relative to PDCD1 and VSIG9 in a model of neoantigen-mediated cancer cell cytolysis demonstrates that the intra-cellular immune checkpoint protein CISH can potentially enhance anti-tumor responses against a broad range of cancer types regardless of PD-L1 biomarker status.

In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4+ TH1 cell response

Findings identify SOCS1 as a major intracellular negative checkpoint of adoptive T cell response, opening new possibilities to optimize CAR-T cell therapy composition and efficacy.

The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients

An overview of the main strategies for TCR-engineering is provided, the selection and expansion of optimal carrier cells for T CR-ACT are described and the next-generation methods for rapid identification of relevant TCR candidates for gene transfer therapy are discussed.

Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors

This review summarizes the fundamental work in the field of TIL therapy and the current landscape and advances of Til clinical trials worldwide and the opportunities and challenges in the development of next-generation TIL are highlighted.

ACT Up TIL Now: The Evolution of Tumor-Infiltrating Lymphocytes in Adoptive Cell Therapy for the Treatment of Solid Tumors

The adoptive cell transfer of autologous tumor-infiltrating lymphocytes has been used in humans for over 30 years to treat metastatic melanoma, and continued modifications are making it increasingly more effective against other types of cancer.

A Novel Cell Therapy for COVID-19 and Potential Future Pandemics: Virus Induced Lymphocytes (VIL)

The data suggest that VIL may represent a novel therapeutic option that warrants further clinical investigation in the armamentarium against COVID-19 and other possible future pandemics.

Epitranscriptomic Approach: To Improve the Efficacy of ICB Therapy by Co-Targeting Intracellular Checkpoint CISH

This study encapsulates the evidence, as a possible strategy, to improve the efficacy of ICB-therapy by co-targeting molecular checkpoints especially N6A-modification machineries which can be reformed into RNA modifying drugs (RMD).

CISH Expression Is Associated with Metastasis-Free Interval in Triple-Negative Breast Cancer and Refines the Prognostic Value of PDL1 Expression

It was demonstrated that high CISH upregulation was associated with better metastasis-free interval, especially when PDL1 was also upregulated, and it was shown that the two-gene model (CISH andPDL1) provided more prognostic information than each gene alone and maintained its prognostic value in multivariate analysis.

Exploiting the CRISPR‐Cas9 gene‐editing system for human cancers and immunotherapy

The application and challenges of CRISPR technology in cancer research and immunotherapy, its advances and prospects for promoting new cell‐based therapeutic beyond immune oncology are discussed.

Emerging Trends in Immunotherapy for Cancer

A comprehensive overview of the development and clinical implementation of various immunotherapy approaches currently being used to treat cancer is presented and the latest developments, emerging trends, limitations, and future promises of cancer immunotherapy are highlighted.



PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.

It is demonstrated that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD- 1 expression in the tumor microenvironment.

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

A relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas and the impact of neoantigens intratumor heterogeneity (ITH) on antitumor immunity is demonstrated.

Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates

It is shown that human lung and colorectal cancer CD8+ TILs can not only be specific for tumour antigens, but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein–Barr virus, human cytomegalovirus or influenza virus).

Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy.

This approach provides a highly sensitive platform to isolate clinically relevant neoantigen-reactive T cells or their TCRs for cancer treatment.

Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics.

It is shown that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells, which results in enhanced persistence of Til after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy.

Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers

A novel strategy was developed to systematically and comprehensively analyze intratumoral T cell responses to defined TP53 hot spot mutations independent of other tumor mutations in 133 new patients with multiple tumor types, to translate cells or their TCR genes into broadly applicable adoptive cellular therapies for common epithelial malignancies.

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.

The findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.

c-Jun overexpression in CAR T cells induces exhaustion resistance

It is concluded that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c- Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.

Cancer neoantigens targeted by adoptive T cell transfer: private no more.

It is shown that a fraction of patients with epithelial cancers mount antigen-specific T cell responses to "hot spot" p53 mutations that in some cases are shared among patients, suggesting that other genes frequently mutated in human cancer can be immunogenic.

TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection

It is shown that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.