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Background and aimsThe role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy.MethodsWe use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry.ResultsWe found that patients’ regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy.ConclusionsOur findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.

This essay examines the role of myth in and as cultural memory through a reading of the novel, Archipelago (2013), by the Trinidadian-British author Monique Roffey. Against conceptions of the Anthropocene as a break from the past—a break that repeats the myth of modernity—I argue that Roffey’s use of cultural memory offers a carnivalesque relation to the world in response to the narrative’s account of climate change trauma. Drawing on Bakhtin’s classic study of the carnival as an occasion for contestation and renewal, as well as Cheryl Lousely’s call for a “carnivalesque ecocriticism,” this essay expands on the recent ecocritical turn to the field of Memory Studies (Buell; Goodbody; Kennedy) to illustrate the way literature mediates between mythic and historical relations to the natural world. As literary expressions, the carnivalesque and the grotesque evoke myth and play in order to expose and transform the social myths which govern relations and administrate difference. Since literature acts as both a producer and reflector of cultural memory, this essay seeks to highlight the literary potential of myth for connecting past traumas to affirmational modes of political engagement., Este ensayo examina el papel del mito en y como memoria cultural analizando la novela Archipelago (2013), escrita por la autora trinitense-británica Monique Roffey. Frente a la idea del Antropoceno como una ruptura con el pasado—una ruptura que repite el mito de la modernidad—este trabajo argumenta que el uso de la memoria cultural de Roffey ofrece una relación carnavalesca con el mundo en respuesta al trauma del cambio climático detallado en la novela. Basando mi argumento en la teoría clásica de Bakhtin sobre el carnaval como una ocasión para la contestación y la renovación, así como la llamada de Cheryl Lousely por una “ecocrítica carnavalesca,” este ensayo amplía el reciente giro de la ecocrítica hacia el campo de los estudios de memoria (Buell; Goodbody; Kennedy) para ilustrar cómo la literatura media entre las relaciones míticas e históricas con el mundo natural. Como expresiones literarias, lo carnavalesco y lo grotesco evocan el mito y el juego para revelar y transformar los mitos sociales que gobiernan las relaciones y gestionan la diferencia. Ya que la literatura actúa tanto como productora y como espejo de la memoria cultural, este ensayo busca destacar el potencial literario del mito para conectar traumas del pasado con modos de compromiso político más afirmativos.