Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer

Salvi, Sandra; Fontana, Vincenzo; Boccardo, Simona; Merlo, Domenico Franco; Margallo, Edoardo; Laurent, Stefania; Morabito, Anna; Rijavec, Erika; Bello, Maria Giovanna Dal; Mora, Marco; Ratto, G. B.; Grossi, Francesco; Truini, Mauro; Pistillo, Maria Pia

doi:10.1007/s00262-012-1211-y

Cited by 117 publications

(108 citation statements)

References 32 publications

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“…36-42 Furthermore, single and combinatorial checkpoint blockade have also shown promise in both preclinical and clinical settings. 10 , 12 , 43-48 In our study, we identify a significant survival benefit with the use of combination PD-1 and TIGIT blockade in the murine GBM model through modulations of both the T cell and myeloid compartments.…”

Section: Discussionmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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Section: Discussionmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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“…Similar low frequencies have been described for tumor-infiltrating T cells in lung cancer. 26 Interestingly, the percentage of CTLA-4 C cells was significantly elevated in tumor samples within the CD4 C subset, potentially reflecting an increase of regulatory T cells. 30 In an additional subset-analysis, CTLA-4 as well as PD-L1 expression was elevated on CD4…”

Section: Cd25mentioning

confidence: 99%

“…17,24 Although the prevailing notion is that ipilimumab targets CTLA-4 on T cells, its exact mode of action is still under discussion, as CTLA-4 can be expressed on regulatory lymphocytes as well as on malignant cells. [25][26][27][28][29] In an early trial investigating the CLTA-4 antibody tremelimumab in metastatic gastric adenocarcinoma, tumor shrinkage with some long-lasting responses have been described. Of note, this study did not report on CTLA-4 expression on primary tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

et al. 2015

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Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted nextgeneration sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumordraining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/ 127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.Abbreviations: CTLA-4, cytotoxic T lymphocyte associated molecule 4; PBMC, peripheral blood mononuclear cells; PD-1, programmed death 1; PD-L1, programmed death 1 ligand 1; TDLN, tumor-draining lymph nodes; UICC, Union International Contre le Cancer.

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“…In one study, CTLA4 was associated with nonsquamous histology but was not prognostic for OS [Salvi et al 2012]. In another study, CTLA4 tumor expression was associated with older age and poor tumor differentiation [Sundar et al 2014;Zheng et al 2010].…”

Section: Targeting Ctla4mentioning

confidence: 99%

Targeting the immune system to treat lung cancer: rationale and clinical experience

Guibert

Delaunay

2015

Ther Adv Respir Dis

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Abstract:The use of immunotherapy that harnesses and enhances the innate powers of the immune system to fight cancer cells represents the most promising new cancer treatment approach since the development of the first chemotherapies and, more recently, targeted therapies. Unexpectedly, lung cancer has recently emerged as an exciting new target for immune-based therapies. Several approaches to immunotherapy for lung cancer have shown promise in early clinical trials and in late-phase development. The most advanced strategies can be split into two main categories: therapeutic vaccines and checkpoint inhibitors. At this time of great expectations, this review provides the reader with an update on the immunotherapies used to treat lung cancer with a focus on the rationale of targeting the immune system. It reports the results from recent major clinical trials, describes new toxicity profiles associated with such drugs, and particularly the role of the pulmonologists in their management. This review provides an overview of the main perspectives within this field.

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Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer

Cited by 117 publications

References 32 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

Targeting the immune system to treat lung cancer: rationale and clinical experience

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