Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses

Huang, Mou Tuan; Nicholson, Lowell T.; Batich, Kristen A.; Swartz, Adam M.; Kopin, David; Wellford, Sebastian; Prabhakar, Vijay K.; Woroniecka, Karolina; Nair, Smita K.; Fecci, Peter E.; Sampson, John H.; Gunn, Michael D.

doi:10.1172/jci128267

Cited by 52 publications

(50 citation statements)

References 78 publications

(105 reference statements)

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“…Interestingly, tumor antigen in metastatic lung sites is redirected from Mϕs to cDCs in CCR2‐deficient mice, indicating that different APCs may compete for tumor antigen 44 . Additionally, monocytes may most effectively contribute to antitumoral immunity, especially in TIMEs with sufficient numbers of cDCs, by transporting antigen to lymphoid organs before transfer to APCs 72 …”

Section: Introductionmentioning

confidence: 99%

Functional crosstalk between T cells and monocytes in cancer and atherosclerosis

Padgett

Araujo

Hedrick

et al. 2020

Journal of Leukocyte Biology

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Monocytes and monocyte‐derived cells, including Mϕs and dendritic cells, exhibit a diverse array of phenotypic states that are dictated by their surrounding microenvironment. These cells direct T cell activation and function via cues that range from being immunosuppressive to immunostimulatory. Solid tumors and atherosclerotic plaques represent two pathological niches with distinct immune microenvironments. While monocytes and their progeny possess a phenotypic spectrum found within both disease contexts, most within tumors are pro‐tumoral and support evasion of host immune responses by tumor cells. In contrast, monocyte‐derived cells within atherosclerotic plaques are usually pro‐atherogenic, pro‐inflammatory, and predominantly directed against self‐antigens. Consequently, cancer immunotherapies strive to enhance the immune response against tumor antigens, whereas atherosclerosis treatments seek to dampen the immune response against lipid antigens. Insights into monocyte‐T cell interactions within these niches could thus inform therapeutic strategies for two immunologically distinct diseases. Here, we review monocyte diversity, interactions between monocytes and T cells within tumor and plaque microenvironments, how certain therapies have leveraged these interactions, and novel strategies to assay such associations.

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Section: Introductionmentioning

confidence: 99%

Functional crosstalk between T cells and monocytes in cancer and atherosclerosis

Padgett

Araujo

Hedrick

et al. 2020

Journal of Leukocyte Biology

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“…[17][18][19] This apparently weak immunogenicity can be due to several reasons, including the absence of appropriate immunological danger signals during immunizations, the suboptimal activation of DCs and/or an inefficient delivery of relevant TAA to resident DC populations responsible for ideal cross-priming of protective CD8 + T cells. [20][21][22] In this report, we tested a vaccine named TRIMELVax consisting in HS-conditioned TRIMEL plus B16F10 cell lysates combined with Concholepas concholepas hemocyanin (CCH) as an adjuvant. The earliest discovered hemocyanin commonly known as keyhole limpet hemocyanin (KLH) is purified from the giant keyhole limpet gastropod Megathura crenulata and has been successfully used as an adjuvant in many clinical protocols.…”

Section: Introductionmentioning

confidence: 99%

A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth

Gleisner

Pereda

Tittarelli

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint blocker (ICB) therapy has shown survival benefits for some patients with cancer. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines offer an attractive alternative. Optimal delivery of multiple tumor-associated antigens combined with potent adjuvants seems to be crucial for vaccine effectiveness.MethodsHere, a prototype for a generic melanoma vaccine, named TRIMELVax, was tested using B16F10 mouse melanoma model. This vaccine is made of heat shock-treated tumor cell lysates combined with the Concholepas concholepas hemocyanin as adjuvant.ResultsWhile B16F10 lysate provides appropriate melanoma-associated antigens, both a generic human melanoma cell lysate and hemocyanin adjuvant contributes with danger signals promoting conventional dendritic type 1 cells (cDC1), activation, phagocytosis and effective antigen cross-presentation. TRIMELVax inhibited tumor growth and increased mice survival, inducing cellular and humoral immune responses. Furthermore, this vaccine generated an increased frequency of intratumor cDC1s but not conventional type 2 dendritic cells (cDC2s). Augmented infiltration of CD3+, CD4+ and CD8+ T cells was also observed, compared with anti-programmed cell death protein 1 (PD-1) monotherapy, while TRIMELVax/anti-PD-1 combination generated higher tumor infiltration of CD4+ T cells. Moreover, TRIMELVax promoted an augmented proportion of PD-1lo CD8+ T cells in tumors, a phenotype associated with prototypic effector cells required for tumor growth control, preventing dysfunctional T-cell accumulation.ConclusionsThe therapeutic vaccine TRIMELVax efficiently controls the weakly immunogenic and aggressive B16F10 melanoma tumor growth, prolonging tumor-bearing mice survival even in the absence of ICB. The strong immunogenicity shown by TRIMELVax encourages clinical studies in patients with melanoma.

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“…These results strongly suggest that the acquisition of antigenic peptides by DCs via Cx43-GJ-mediated communications with tumor cells is far more effective than standard pathways for antigen loading during the generation of protective DC vaccines. In this regard, recently, it has been shown that Cx43-mediated antigen transfer impact the efficacy of APC-based cancer vaccines, where the activation of T cells requires the priming activity of endogenous DCs, which are activated through the transfer of peptides via Cx43-GJs from ex vivo loaded monocytes to endogenous CD8 + splenic DCs [58]. The formal demonstration for the existence of a Cx43-mediated antigenic peptide transfer pathway is highly relevant for the design of successful anti-cancer immunotherapy treatments [58].…”

Section: Cx43 Channels Also Impact Dc-mediated T Cell Activation By Amentioning

confidence: 99%

“…In this regard, recently, it has been shown that Cx43-mediated antigen transfer impact the efficacy of APC-based cancer vaccines, where the activation of T cells requires the priming activity of endogenous DCs, which are activated through the transfer of peptides via Cx43-GJs from ex vivo loaded monocytes to endogenous CD8 + splenic DCs [58]. The formal demonstration for the existence of a Cx43-mediated antigenic peptide transfer pathway is highly relevant for the design of successful anti-cancer immunotherapy treatments [58]. Interestingly, DCs can also acquire tumor antigens from apoptotic tumor cells via a direct GJ-mediated mechanism [59].…”

Section: Cx43 Channels Also Impact Dc-mediated T Cell Activation By Amentioning

confidence: 99%

Connexin-Mediated Signaling at the Immunological Synapse

Tittarelli

Navarrete

Gleisner

et al. 2020

IJMS

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The immunological synapse (IS) is an intercellular communication platform, organized at the contact site of two adjacent cells, where at least one is an immune cell. Functional IS formation is fundamental for the modulation of the most relevant immune system activities, such as T cell activation by antigen presenting cells and T cell/natural killer (NK) cell-mediated target cell (infected or cancer) killing. Extensive evidence suggests that connexins, in particular connexin-43 (Cx43) hemichannels and/or gap junctions, regulate signaling events in different types of IS. Although the underlying mechanisms are not fully understood, the current evidence suggests that Cx43 channels could act as facilitators for calcium ions, cyclic adenosine monophosphate, and/or adenosine triphosphate uptake and/or release at the interface of interacting cells. These second messengers have relevant roles in the IS signaling during dendritic cell-mediated T and NK cell activation, regulatory T cell-mediated immune suppression, and cytotoxic T lymphocyte or NK cell-mediated target tumor cell killing. Additionally, as the cytoplasmic C-terminus domain of Cx43 interacts with a plethora of proteins, Cx43 may act as scaffolds for integration of various regulatory proteins at the IS, as suggested by the high number of Cx43-interacting proteins that translocate at these cell-cell interface domains. In this review, we provide an updated overview and analysis on the role and possible underlying mechanisms of Cx43 in IS signaling.

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Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses

Cited by 52 publications

References 78 publications

Functional crosstalk between T cells and monocytes in cancer and atherosclerosis

Functional crosstalk between T cells and monocytes in cancer and atherosclerosis

A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth

Connexin-Mediated Signaling at the Immunological Synapse

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