Role of LFA-1 and ICAM-1 in Cancer

Reina, Manuel; Espel, Enric

doi:10.3390/cancers9110153

Cited by 100 publications

(64 citation statements)

References 125 publications

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“…31,36–38 Consistent with this, transfection of ICAM-1 into colorectal cancer cell lines inhibits tumor growth and metastasis. 39 In addition, the production of prostaglandin E2 in the tumor microenvironment downregulates the expression of ICAM-1 in tumor cells, reducing the cytotoxic effects of T cells.…”

Section: Discussionsupporting

confidence: 59%

“…31 Indeed, administration of anti-LFA-1 antibodies completely abrogates the efficacy of adoptive immunotherapy, 32 suggesting an important contribution of LFA-1 in tumor immunology. However, no modulators that increase the affinity of LFA-1 have been applied to antitumor activity because they may have deleterious effects as a result of unwanted binding of T cells to non-target, ICAM-positive cells or tissues.…”

Section: Discussionmentioning

confidence: 99%

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Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

et al. 2018

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Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an ‘inside-out’ activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2–actin–LFA-1 axis is an effective strategy to potentiate the adoptive T-cell immunotherapy.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

et al. 2018

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“…As an illustration, Cavatak binds to the intercellular adhesion molecule 1 (ICAM-1) whose expression is limited to normal endothelial and immune cells and to several tumors (eg, melanoma, colorectal, breast, and lung cancers). 50 Consequently, MG1’s broad tropism is an undeniable asset to treat virtually any malignancy. However, it comes along with infection of normal tissues that may raise safety concerns.…”

Section: Discussionmentioning

confidence: 99%

Development and applications of oncolytic Maraba virus vaccines

Pol¹,

Atherton²,

Bridle³

et al. 2018

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Oncolytic activity of the MG1 strain of the Maraba vesiculovirus has proven efficacy in numerous preclinical cancer models, and relied not only on a direct cytotoxicity but also on the induction of both innate and adaptive antitumor immunity. To further expand tumor-specific T-cell effector and long-lasting memory compartments, we introduced the MG1 virus in a prime-boost cancer vaccine strategy. To this aim, a replication-incompetent adenoviral [Ad] vector together with the oncolytic MG1 have each been armed with a transgene expressing a same tumor antigen. Immune priming with the Ad vaccine subsequently boosted with the MG1 vaccine mounted tumor-specific responses of remarkable magnitude, which significantly prolonged survival in various murine cancer models. Based on these promising results, we validated the safety profile of the Ad:MG1 oncolytic vaccination strategy in nonhuman primates and initiated clinical investigations in cancer patients. Two clinical trials are currently under way (NCT02285816; NCT02879760). The present review will recapitulate the discoveries that led to the development of MG1 oncolytic vaccines from bench to bedside.

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“…A death pathway that could be potentially exploited by cancer cells. Indeed, some studies report that the increased expression of ICAM-1 on tumour cells correlates with a more aggressive cancer [83].…”

Section: Lfa-1 Mediated Inhibition Of Nk Cell Degranulation: Multi-fumentioning

confidence: 99%

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

Zamai

Zotto

Buccella

et al. 2020

Cells

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The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment.

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Role of LFA-1 and ICAM-1 in Cancer

Cited by 100 publications

References 125 publications

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

Development and applications of oncolytic Maraba virus vaccines

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

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