evere infection with COVID-19 has been linked to immune dysregulation, including impaired or delayed production of type I and type III interferons 1-5 , marked lymphopenia [6][7][8][9][10] and a paradoxical increase in pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6 1,4,6,[11][12][13] . Alteration of T cell compartments include increases in effector and activated CD4 and CD8 T cells [14][15][16][17] , CD8 + T cells contribute to survival in patients with COVID-19 and hematologic cancer

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.

The discovery that androgens play an important role in the progression of prostate cancer led to the development of androgen deprivation therapy (ADT) as a first line of treatment. However, paradoxical growth inhibition has been observed in a subset of prostate cancer upon administration of supraphysiologic levels of testosterone (SupraT), both experimentally and clinically. Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive prostate cancer cells. This was initiated by the induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activated nucleic acid sensors converge on NFκB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT resulted in increased migration of cytotoxic immune cells to tumor beds in xenograft models and patient tumors. Collectively, these findings indicate that SupraT may inhibit a subset of prostate cancer by activating nucleic acid sensors and downstream immune signaling. Significance: This study demonstrates that supraphysiologic testosterone induces two parallel autophagy-mediated processes, ferritinophagy and nucleophagy, which then activate nucleic acid sensors to drive immune signaling pathways in prostate cancer.

Underrepresentation of minority groups in the oncology physician workforce is a pressing issue that may contribute to disparities in cancer research, clinical care, and patient outcomes. To address this, we highlight the role of medical culture and institutions in perpetuating a range of barriers that lead to the persistent underrepresentation of minority medical trainees and physicians. These barriers include an exclusionary medical culture, bias in measures of merit, financial barriers to medical subspecialty training, underrecognition of achievement, and poor representation and satisfaction among underrepresented faculty. Furthermore, we suggest a more intentional approach to diversity that values both recruitment of underrepresented undergraduates and early medical students and retention of internal medicine trainees, hematology-oncology fellows, and faculty. To counteract deeply embedded structural racism that hampers diversity efforts, this multifaceted approach will require cultural transformation of our medical institutions at all levels, including increased institutional transparency, mandatory evidence-based bias training, acknowledgment of varied achievements, changes in recruitment practices, and reinvigoration of pipeline development programs with a focus on financial support. Taken in combination, programs should recognize the scope of deterrents to representation and develop program-specific, longitudinal interventions to promote more successful diversity initiatives within the field of oncology. The Oncologist 2021;26:630-634 Implications for Practice: The medical profession recognizes the value of physician workforce diversity in improving the quality of both medical education and patient care. In return, medical schools and training programs invest in recruitment programs focused on candidates who are underrepresented in medicine. In the field of oncology, where stark racial and ethnic disparities in care and health outcomes are well-defined, measures of minority physician representation remain especially stagnant. This study clearly defines the barriers that limit the effectiveness of such programs and provides recommendations to achieve the necessary workforce diversity in oncology.