The Dynamic Entropy of Tumor Immune Infiltrates: The Impact of Recirculation, Antigen-Specific Interactions, and Retention on T Cells in Tumors

Blair, Tiffany C.; Alice, Alejandro F.; Zebertavage, Lauren; Crittenden, Marka R.; Gough, Michael

doi:10.3389/fonc.2021.653625

Cited by 15 publications

(28 citation statements)

References 210 publications

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“…One strong caveat in the explant approach is that it is dependent on the response pattern of immune cells already present in the tumor environment. If the immunotherapy is dependent on the activation of immune cells in the circulation, or in secondary lymphatics, the explant approach may miss critical responses (52). As discussed above, many of the critical immune cells are already resident in tumors (7) and some therapies can function without systemic circulation of T cells (5,6,53).…”

Section: Discussionmentioning

confidence: 99%

Explant Modeling of the Immune Environment of Head and Neck Cancer

et al. 2021

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Patients exhibit distinct responses to immunotherapies that are thought to be linked to their tumor immune environment. However, wide variations in outcomes are also observed in patients with matched baseline tumor environments, indicating that the biological response to treatment is not currently predictable using a snapshot analysis. To investigate the relationship between the immune environment of tumors and the biological response to immunotherapies, we characterized four murine head and neck squamous cell carcinoma (HNSCC) models on two genetic backgrounds. Using tumor explants from those models, we identified correlations between the composition of infiltrating immune cells and baseline cytokine profiles prior to treatment. Following treatment with PD-1 blockade, CTLA-4 blockade, or OX40 stimulation, we observed inter-individual variability in the response to therapy between genetically identical animals bearing the same tumor. These distinct biological responses to treatment were not linked to the initial tumor immune environment, meaning that outcome would not be predictable from a baseline analysis of the tumor infiltrates. We similarly performed the explant assay on patient HNSCC tumors and found significant variability between the baseline environment of the tumors and their response to therapy. We propose that tumor explants provide a rapid biological assay to assess response to candidate immunotherapies that may allow matching therapies to individual patient tumors. Further development of explant approaches may allow screening and monitoring of treatment responses in HNSCC.

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Section: Discussionmentioning

confidence: 99%

Explant Modeling of the Immune Environment of Head and Neck Cancer

et al. 2021

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“…Importantly, we demonstrate that tumor-specific cells expand in number in the peripheral circulation and accumulate at the tumor, indicating that lymphocyte recirculation is fully functional when T-cells are delivered to the resection site. Recirculation is critical to effectively detect tumors that may additionally be present at distant sites, and sustain systemic anti-tumor immunity [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, when T-cells were delivered locally in a biomaterial, there was no negative impact on their numbers in the systemic circulation, suggesting that this platform has the potential to provide systemic immunosurveillance for distant disease. Further studies are necessary to map the activation and distribution pattern of the T-cells to understand the effect of local delivery on activation in the local site versus draining lymphatics, and the effect of this therapy on recirculation kinetics [ 10 ]. In HNSCC, resection of the advanced tumor, followed by adjuvant therapy, will fail in approximately half of the patients, with 20-30% of patients failing locally [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, systemically applied T-cells are likely to evenly distribute between tissues and secondary lymphoid organs throughout the patient while their target antigen is restricted to a specific lymphatic drainage system. This may result in an immediate reduction in the proportion of transferred cells that can meet their cognate antigen in the narrow time window [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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A platform for locoregional T-cell immunotherapy to control HNSCC recurrence following tumor resection

et al. 2021

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Surgical resection of head and neck squamous-cell carcinoma (HNSCC) is associated with high rates of local and distant recurrence, partially mitigated by adjuvant therapy. A pre-existing immune response in the patient's tumor is associated with better outcomes following treatment with conventional therapies, but improved options are needed for patients with poor anti-tumor immunity. We hypothesized that local delivery of tumor antigen-specific T-cells into the resection cavity following surgery would direct T-cells to residual antigens in the margins and draining lymphatics and present a platform for T-cell-targeted immunotherapy. We loaded T-cells into a biomaterial that conformed to the resection cavity and demonstrated that it could release T-cells that retained their functional activity in-vitro, and in a HNSCC model in-vivo. Locally delivered T-cells loaded in a biomaterial were equivalent in control of established tumors to intravenous adoptive T-cell transfer, and resulted in the systemic circulation of tumor antigen-specific T-cells as well as local accumulation in the tumor. We demonstrate that adjuvant therapy with anti-PD1 following surgical resection was ineffective unless combined with local delivery of T-cells. These data demonstrate that local delivery of tumor-specific T-cells is an efficient option to convert tumors that are unresponsive to checkpoint inhibitors to permit tumor cures.

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“…This may allow creating a more favorable environment for CAR-T cells and longer CAR-T cell persistence and efficacy [ 97 ]. This may favor CAR-T cells acquisition of memory cell’s function [ 98 , 99 ], which may provide long-term immune recognition of cancer [ 100 ] ( Figure 5 ).…”

Section: Cancer-associated Immune Cell Populationsmentioning

confidence: 99%

Cancer-Homing CAR-T Cells and Endogenous Immune Population Dynamics

Guerra

Pietro

Basile

et al. 2021

IJMS

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Chimeric antigen receptor (CAR) therapy is based on patient blood-derived T cells and natural killer cells, which are engineered in vitro to recognize a target antigen in cancer cells. Most CAR-T recognize target antigens through immunoglobulin antigen-binding regions. Hence, CAR-T cells do not require the major histocompatibility complex presentation of a target peptide. CAR-T therapy has been tremendously successful in the treatment of leukemias. On the other hand, the clinical efficacy of CAR-T cells is rarely detected against solid tumors. CAR-T-cell therapy of cancer faces many hurdles, starting from the administration of engineered cells, wherein CAR-T cells must encounter the correct chemotactic signals to traffic to the tumor in sufficient numbers. Additional obstacles arise from the hostile environment that cancers provide to CAR-T cells. Intense efforts have gone into tackling these pitfalls. However, we argue that some CAR-engineering strategies may risk missing the bigger picture, i.e., that a successful CAR-T-cell therapy must efficiently intertwine with the complex and heterogeneous responses that the body has already mounted against the tumor. Recent findings lend support to this model.

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The Dynamic Entropy of Tumor Immune Infiltrates: The Impact of Recirculation, Antigen-Specific Interactions, and Retention on T Cells in Tumors

Cited by 15 publications

References 210 publications

Explant Modeling of the Immune Environment of Head and Neck Cancer

Explant Modeling of the Immune Environment of Head and Neck Cancer

A platform for locoregional T-cell immunotherapy to control HNSCC recurrence following tumor resection

Cancer-Homing CAR-T Cells and Endogenous Immune Population Dynamics

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