PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells

Liotti, Federica; Kumar, Narender; Prevete, Nella; Marotta, Maria; Sorriento, Daniela; Ieranò, Caterina; Ronchi, Andrea; Marino, Federica Zito; Moretti, Sonia; Colella, Renato; Puxeddu, Efisio; Paladino, Simona; Kano, Yoshihito; Ohh, Michael; Scala, Stefania; Melillo, Rosa Marina

doi:10.1186/s13046-020-01818-1

Cited by 43 publications

(23 citation statements)

References 52 publications

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“…PD-1 activation in T cells inhibits MAPK signalling attenuating pro-survival signalling in T cells 66 . However, PD-1 activates MAPK signalling in thyroid cancer cells promoting tumour cell survival 67 . Additionally, STAT3 signalling regulates PD-L1 expression on the surface of colon cancer cells 39 however, STAT3 blockade had no significant effect on PD-L1 expression in OAC cells in this study.…”

Section: Discussionmentioning

confidence: 99%

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

Davern

Brien

McGrath

et al. 2022

Sci Rep

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Chemotherapy upregulates immune checkpoint (IC) expression on the surface of tumour cells and IC-intrinsic signalling confers a survival advantage against chemotherapy in several cancer-types including oesophageal adenocarcinoma (OAC). However, the signalling pathways mediating chemotherapy-induced IC upregulation and the mechanisms employed by ICs to protect OAC cells against chemotherapy remain unknown. Longitudinal profiling revealed that FLOT-induced IC upregulation on OE33 OAC cells was sustained for up to 3 weeks post-treatment, returning to baseline upon complete tumour cell recovery. Pro-survival MEK signalling mediated FLOT-induced upregulation of PD-L1, TIM-3, LAG-3 and A2aR on OAC cells promoting a more immune-resistant phenotype. Single agent PD-1, PD-L1 and A2aR blockade decreased OAC cell viability, proliferation and mediated apoptosis. Mechanistic insights demonstrated that blockade of the PD-1 axis decreased stem-like marker ALDH and expression of DNA repair genes. Importantly, combining single agent PD-1, PD-L1 and A2aR blockade with FLOT enhanced cytotoxicity in OAC cells. These findings reveal novel mechanistic insights into the immune-independent functions of IC-intrinsic signalling in OAC cells with important clinical implications for boosting the efficacy of the first-line FLOT chemotherapy regimen in OAC in combination with ICB, to not only boost anti-tumour immunity but also to suppress IC-mediated promotion of key hallmarks of cancer that drive tumour progression.

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Section: Discussionmentioning

confidence: 99%

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

Davern

Brien

McGrath

et al. 2022

Sci Rep

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“…The understanding of mechanisms underlying the proliferation and regulation of T-cells paved the way to identify specific targets (the ICs), against which antibodies acting either as agonists for co-stimulatory receptors or antagonists for inhibitory receptors were generated, in order to improve immune responses of tumor infiltrating lymphocytes [3,4,9,11,40]. Recently, it has been reported the expression of ICs not only on immune cell populations [5,6,14], but also on cancer cells, where they seem to promote the evasion from anti-tumor immune responses [29].…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported in literature that some Immune Checkpoints, such as PD-1, PD-L1 and CTLA-4, are expressed not only on immune cells but also on many different types of tumors, and that immunomodulatory mAbs specific for these targets can affect tumor cell viability even in the absence of immune cells [6,[28][29][30][31]. Here, we investigated the effects of anti-PD-1, anti-PD-L1 and anti-CTLA-4 immunomodulatory mAbs on different tumor cells by choosing in particular breast and lung cell lines, as many ongoing clinical trials are evaluating the efficacy of immunomodulatory mAbs on these tumors [32][33][34].…”

Section: Effects Of Different Immunomodulatory Mabs On a Panel Of Tum...mentioning

confidence: 99%

Immunomodulatory mAbs as Tools to Investigate on Cis-Interaction of PD-1/PD-L1 on Tumor Cells and to Set Up Methods for Early Screening of Safe and Potent Combinatorial Treatments

Vetrei

Passariello

Froechlich

et al. 2021

Cancers

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Antibodies targeting Immune Checkpoints (IC) on tumor infiltrating lymphocytes improve immune responses against cancer. Recently, the expression of some ICs has also been reported on cancer cells. We used the clinically validated Ipilimumab and Nivolumab and other novel human antibodies targeting Cytotoxic T- lymphocyte-antigen 4 (CTLA-4), Programmed Death receptor-1 (PD-1) and Programmed Death Ligand 1 (PD-L1) to shed light on the functions of these ICs in cancer cells. We show here for the first time that all these antagonistic mAbs are able to reduce Erk phosphorylation and, unexpectedly, to induce a significant increase of ICs expression on tumor cells, involving a hyperphosphorylation of NF-kB. On the contrary, agonistic PD-L1 and PD-1 recombinant proteins showed opposite effects by leading to a significant reduction of PD-1 and PD-L1, thus also suggesting the existence of a crosstalk in tumor cells between multiple ICs. Since the immunomodulatory mAbs show their higher anti-tumor efficacy by activating lymphocytes against cancer cells, we also investigated whether it was possible to identify the most efficient combinations of immunomodulatory mAbs for achieving potent anti-tumor efficacy associated with the lowest adverse side effects by setting up novel simple and predictive in vitro models based on co-cultures of tumor cells or human fetal cardiomyocytes with lymphocytes. We demonstrate here that novel combinations of immunomodulatory mAbs with more potent anti-cancer activity than Ipilimumab and Nivolumab combination can be identified with no or lower cardiotoxic side effects. Thus, we propose these co-cultures-based assays as useful tools to test also other combinatorial treatments of emerging immunomodulatory mAbs against different ICs for the early screening of most potent and safe combinatorial therapeutic regimens.

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“…The combination of PD-1 with PD-L1, through the PI3K-AKT signaling pathway, releases immunosuppressive signals to inhibit the activation and proliferation of T cells, as well as to induce T-cell tolerance and exhaustion ( 49 , 71 ). It can also directly affect the proliferation of cytotoxic T cells through the SH2 containing protein tyrosine phosphatase-2/Ras/MAPK signaling pathway ( 72 ). PD-L1 alone or in combination with LAG-3 blocker and CXCL13 can contribute to delayed tumor growth and is associated with survival benefits ( 73 , 74 ).…”

Section: Immune Checkpoints and Tumor Immunotherapymentioning

confidence: 99%

Role of the tumor immune microenvironment in tumor immunotherapy (Review)

et al. 2021

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Tumor immunotherapy is considered to be a novel and promising therapy for tumors and it has recently become a hot research topic. The clinical success of tumor immunotherapy has been notable, but it has been less than totally satisfactory because tumor immunotherapy has performed poorly in numerous patients although it has shown appreciable efficacy in some patients. A minority of patients demonstrate durable responses but the majority of patients do not respond to tumor immunotherapy as the tumor immune microenvironment is different in different patients for different tumor types. The success of tumor immunotherapy may be affected by the heterogeneity of the tumor immune microenvironment and its components, as these vary widely during neoplastic progression. The deepening of research and the development of technology have improved our understanding of the complexity and heterogeneity of the tumor immune microenvironment and its components, and their effects on response to tumor immunotherapy. Therefore, investigating the tumor immune microenvironment and its components and elucidating their association with tumor immunotherapy should improve the ability to study, predict and guide immunotherapeutic responsiveness, and uncover new therapeutic targets.

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PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells

Cited by 43 publications

References 52 publications

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

PD-1 blockade enhances chemotherapy toxicity in oesophageal adenocarcinoma

Immunomodulatory mAbs as Tools to Investigate on Cis-Interaction of PD-1/PD-L1 on Tumor Cells and to Set Up Methods for Early Screening of Safe and Potent Combinatorial Treatments

Role of the tumor immune microenvironment in tumor immunotherapy (Review)

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