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Priming and Propagating Anti-tumor Immunity: Focal Hypofractionated Radiation for in Situ Vaccination and Systemic Targeted Radionuclide Theranostics for Immunomodulation of Tumor Microenvironments.

ABSTRACT: Recent preclinical and clinical studies have elucidated mechanisms whereby radiation therapy influences the anti-tumor immune response. Immunogenic cell death and phenotypic changes in tumor cells surviving radiation may underlie this effect and contribute to the capacity of radiation to elicit an in situ tumor vaccine effect. In situ vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a source of enhanced antigen recognition for the purpose of augmenting a systemic anti-tumor immune response. Capitalizing on the in situ vaccine effect of radiation, several groups have demonstrated anti-tumor efficacy in preclinical models by combining radiation with immune checkpoint blockade. Local delivery of immune adjuvants and/or immune stimulatory cytokines via direct injection into the radiated tumor microenvironment may further increase the in situ vaccine capacity of radiation therapy. However, recent studies suggest that in some contexts this effect is antagonized by the presence of distant untreated sites of disease that may dampen the systemic immune response generated by in situ vaccination through a phenomenon termed concomitant immune tolerance. Concomitant immune tolerance may be overcome by delivering radiation to all sites of metastatic disease, however this is often not possible to safely achieve using external beam radiation therapy without considerable risk of lymphopenia that would negate the immune effects of in situ vaccination. For patients with widespread metastatic disease, alternative strategies may include systemic treatment with targeted radionuclide therapies alone or in combination with an external beam radiation therapy-based in situ vaccine approach.

SUBMITTER: Jagodinsky JC

PROVIDER: S-EPMC7286051 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM) algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM) and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which occurred in spatially distinct microenvironments of primary tumors. We show how machine-learning analysis can classify heterogeneous microenvironments in vivo to enable prediction of motility phenotypes and tumor cell fate. The ability to predict the locations of tumor cell behavior leading to metastasis in breast cancer models may lead towards understanding the heterogeneity of response to treatment.

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Priming and Propagating Anti-tumor Immunity: Focal Hypofractionated Radiation for in Situ Vaccination and Systemic Targeted Radionuclide Theranostics for Immunomodulation of Tumor Microenvironments.

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