Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies

Pitts, Stephanie C.; Schlom, Jeffrey; Donahue, Renee N.

doi:10.1186/s13046-024-03074-z

Cited by 3 publications

(1 citation statement)

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“…These include sPD-L1, sPD1, sCTLA4, sCD80, sTIM3, sLAG3, sB7-H3, sBTLA and sHVEM. These checkpoints are generated by alternative splicing or proteolytic processes and play an important role in immune regulation, are involved in the development and prognosis of cancer and are considered potential biomarkers and therapeutic targets [ 32 ]. They are also ascribed similar functions to the membrane-bound forms.…”

Section: Discussionmentioning

confidence: 99%

The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators

Ries,

Trumet,

Hahn

et al. 2024

IJMS

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In oral squamous cell carcinoma (OSCC) tissues, an immunotolerant situation triggered by immune checkpoints (ICPs) can be observed. Immune checkpoint inhibitors (ICIs) against the PD1/PD-L axis are used with impressive success. However, the response rate is low and the development of acquired resistance to ICI treatment can be observed. Therefore, new treatment strategies especially involving immunological combination therapies need to be developed. The novel negative immune checkpoint BTLA has been suggested as a potential biomarker and target for antibody-based immunotherapy. Moreover, improved response rates could be displayed for tumor patients when antibodies directed against BTLA were used in combination with anti-PD1/PD-L1 therapies. The aim of the study was to check whether the immune checkpoint BTLA is overexpressed in OSCC tissues compared to healthy oral mucosa (NOM) and could be a potential diagnostic biomarker and immunological target in OSCC. In addition, correlation analyses with the expression of other checkpoints should clarify more precisely whether combination therapies are potentially useful for the treatment of OSCC. A total of 207 tissue samples divided into 2 groups were included in the study. The test group comprised 102 tissue samples of OSCC. Oral mucosal tissue from 105 healthy volunteers (NOM) served as the control group. The expression of two isoforms of BTLA (BTLA-1/2), as well as PD1, PD-L1/2 and CD96 was analyzed by RT-qPCR. Additionally, BTLA and CD96 proteins were detected by IHC. Expression levels were compared between the two groups, the relative differences were calculated, and statistical relevance was determined. Furthermore, the expression rates of the immune checkpoints were correlated to each other. BTLA expression was significantly increased in OSCC compared to NOM (pBTLA_1 = 0.003; pBTLA_2 = 0.0001, pIHC = 0.003). The expression of PD1, its ligands PD-L1 and PD-L2, as well as CD96, were also significantly increased in OSCC (p ≤ 0.001). There was a strong positive correlation between BTLA expression and that of the other checkpoints (p < 0.001; ρ ≥ 0.5). BTLA is overexpressed in OSCC and appears to be a relevant local immune checkpoint in OSCC. Thus, antibodies directed against BTLA could be potential candidates for immunotherapies, especially in combination with ICI against the PD1/PD-L axis and CD96.

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Section: Discussionmentioning

confidence: 99%

The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators

Ries,

Trumet,

Hahn

et al. 2024

IJMS

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Novel immunotherapy for multiple solid cancers using an Anti-HVEM blocking monoclonal antibody

Galore-Haskel,

Merhavi-Shoham,

Shapiro

et al. 2024

Preprint

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INTRODUCTIONImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their efficacy remains limited. Therefore, there is a clear need for new anti-tumor agents. HVEM (Herpes Virus Entry Mediator) plays a regulatory role in immunity, making it a promising cancer therapeutic target.EXPERIMENTAL DESIGNWe have developed Anti-4CB1, a fully human HVEM-BTLA and HVEM-CD160 blocking mAb and tested its anti-tumor activity in variousin-vitro, ex-vivoandin-vivomodels, alone or in combination with Anti-PD1. Finally, we analyzed HVEM expression in serum samples and melanoma tumor tissues and its correlation with HVEM and PD1 blockade treatment response.RESULTSIn-vitroassays demonstrated enhanced melanoma cell killing by autologous TILs in the presence of Anti-4CB1. In addition, Anti-4CB1 significantly increased cytotoxicity by up to 233% in a variety ofex-vivocancer tissue samples of different indications. Notably, Anti-4CB1 demonstrated effectiveness in samples where Anti-PD1 was ineffective. In addition, significant anti-tumor activity at 10 mg/kg in combination with Anti-PD1 (TGI 95% p=0.0001) or at 25 mg/kg as monotherapy (TGI 50% p=0.0096) was demonstrated in a colon carcinoma transgenic mice model. Moreover, significant anti-tumor activity was observed in a mouse ImmunoGraft model (TGI 53% p=0.0102 as monotherapy). Finally, we demonstrated that HVEM expression correlated with response to Anti-HVEM and Anti-PD1 treatments.DISCUSSIONWe describe the development of Anti-4CB1, a fully human anti-HVEM mAb, blocking HVEM-BTLA and HVEM-CD160 human interactions and enhancing lymphocytes cytotoxicity against various cancer cellsex-vivo.In-vivo,Anti-4CB1 showed promising anti-tumor effects, particularly in combination with Anti-PD1, suggesting its therapeutic potential. Finally, HVEM expression may serve as a predictive marker for Anti-HVEM and Anti-PD1 treatments response, offering potential diagnostic utility in patient selection for these immunotherapies. These results support Anti-4CB1 potential as an anti-cancer therapeutic agent.Translational RelevanceThe discovery of immune checkpoint inhibitors (ICIs), marks a significant breakthrough in cancer therapy. However, despite the remarkable success of current ICIs targeting CTLA4 and PD1/PD-L1 pathways, a significant proportion of patients fail to respond or develop resistance. Therefore, the search for novel ICIs is crucial for advancing cancer immunotherapy. Anti-HVEM emerged as a promising candidate, as we demonstrate inex-vivoandin-vivomodels, its ability to block the HVEM-BTLA interaction, resulting in enhanced antitumor immune responses in solid tumors, alone or in combination with existing ICIs, to improve treatment outcomes. Moreover, the correlation between HVEM expression and treatment responses highlight its potential as an attractive target for biomarker-driven therapies. Investigating HVEM as an ICI offers a promising path to expand therapeutic options, personalize treatment approaches, address the evolving challenges in cancer immunotherapy and improve patient outcomes.

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Fighting Pancreatic Cancer with a Vaccine-Based Winning Combination: Hope or Reality?

Brugiapaglia,

Spagnolo,

Intonti

et al. 2024

Cells

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Pancreatic adenocarcinoma (PDA) represents the fourth leading cause of cancer-related mortality in the USA. Only 20% of patients present surgically resectable and potentially curable tumors at diagnosis, while 80% are destined for poor survival and palliative chemotherapy. Accordingly, the advancement of innovative and effective therapeutic strategies represents a pivotal medical imperative. It has been demonstrated that targeting the immune system represents an effective approach against several solid tumors. The immunotherapy approach encompasses a range of strategies, including the administration of antibodies targeting checkpoint molecules (immune checkpoint inhibitors, ICIs) to disrupt tumor suppression mechanisms and active immunization approaches that aim to stimulate the host’s immune system. While vaccines have proved effective against infectious agents, vaccines for cancer remain an unfulfilled promise. Vaccine-based therapy targeting tumor antigens has the potential to be a highly effective strategy for initiating and maintaining T cell recognition, enhancing the immune response, and ultimately promoting cancer treatment success. In this review, we examined the most recent clinical trials that employed diverse vaccine types to stimulate PDA patients’ immune systems, either independently or in combination with chemotherapy, radiotherapy, ICIs, and monoclonal antibodies with the aim of ameliorating PDA patients’ quality of life and extend their survival.

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Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies

Cited by 3 publications

References 246 publications

The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators

The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators

Novel immunotherapy for multiple solid cancers using an Anti-HVEM blocking monoclonal antibody

Fighting Pancreatic Cancer with a Vaccine-Based Winning Combination: Hope or Reality?

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