key: cord-0748637-ldjugbpj authors: Latif, Muhammad Bilal; Shukla, Sudhanshu; Estrada, Perla Mariana Del Rio; Ribeiro, Susan Pereira; Sekaly, Rafick Pierre; Sharma, Ashish Arunkumar title: Immune mechanisms in cancer patients that lead to poor outcomes of SARS-CoV-2 infection date: 2021-12-03 journal: Transl Res DOI: 10.1016/j.trsl.2021.12.001 sha: dcb11b31ea62df5db6f25085d1f96d5dc31b2d82 doc_id: 748637 cord_uid: ldjugbpj Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits distinct mechanisms of immune dysfunction, associated with distinct systemic features of hot (T-cell-inflamed/infiltrated) and cold (Non-T-cell-inflamed/infiltrated) tumors. The former show hyper immune activated cells and a highly inflammatory environment while, contrastingly, the latter show the profile of a senescent/quiescent immune system. Thus, the evolution of SARS-CoV-2 infection in different types of cancers can show distinct trajectories which could lead to a variety of clinical and pathophysiological outcomes. The altered immunological environment including cytokines that characterizes hot and cold tumors will lead to different mechanisms of immune dysfunction, which will result in downstream effects on the course of SARS-CoV-2 infection. This review will focus on defining the known contributions of soluble pro- and anti-inflammatory mediators on immune function including altered T-cells and B-cells responses and as well on how these factors modulate the expression of SARS-CoV-2 receptor ACE2, TMPRSS2 expression, and lymph node fibrosis in cancer patients. We will propose immune mechanisms that underlie the distinct courses of SARS-CoV-2 infection in cancer patients and impact on the success of immune based therapies that have significantly improved cancer outcomes. Better understanding of the immune mechanisms prevalent in cancer patients that are associated to the outcomes of SARS-CoV-2 infection will help to identify the high-risk cancer patients and develop immune-based approaches to prevent significant adverse outcomes by targeting these pathways. Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted 19 by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 20 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits to decipher immune responses that govern the development of specific cancers, associated therapies 52 and comorbidities [6, 7] . 53 The severity of COVID-19 disease in cancer patients is partly a function of the etiology, type (hot 54 vs cold tumors, where hot tumors have an immunologically active microenvironment), stage and 55 anatomical location of the tumor [4, [8] [9] [10] [11] [12] . These factors along with treatment regimens play a crucial 56 role in diversifying the immune landscape of a malignancy [8, 12] . Indeed characterized as "non-inflamed" or "immune-deserts" and present with a microenvironment that 136 presents striking features of T-cell r exclusion from the TME [12, 63-65, 68-70]. In the context of SARS-137 CoV-2 infection, it can be speculated that hot tumors (like lung cancer) that are immunologically active 138 and anatomically primed will fuel the systemic inflammatory responses observed during SARS-CoV-2 139 infection (Fig. 3) . However, the exact mechanisms driving adverse outcomes with each cancer (with or 140 without therapy) are yet to be elucidated. 141 To understand the impact of these heterogenous cancer etiologies on COVID-19 outcomes, it is 143 important to first elucidate their impact on SARS-CoV-2 entry/infection and existing or resulting immune 144 cascades. Expression of ACE2 (the viral entry receptor) in lung epithelial was shown to be higher in older 145 subjects, smokers and/or subjects suffering from smoking related disorders like chronic obstructive 146 pulmonary disease (COPD) [3, 13, 71-73]. Moreover, expression of TMPRSS2, a membrane-bound serine 147 protease known to synergize with ACE2 to promote SARS-CoV-2 entry, has also been observed to be 148 highly expressed in prostate cancer (cold cancer), where it is upregulated by androgen receptor (AR) [74-149 76]. Interestingly, in two recent studies, prostate cancer (cold cancer) patients not treated with 150 androgen deprivation therapy (ADT) were more likely to be infected by SARS-CoV-2, suggesting a 151 possible relation of the increased expression of TMPRSS2 and the development of severe COVID-19 in 152 patients with cold tumors like prostate cancer [17, 77] . Based on these data, it can be hypothesized that 153 the increased expression of ACE2 and TMPRSS2, mainly due to pro-inflammatory conditions, in subjects 154 with factors known to be associated with lung cancer incidence could lead to increased viral titers and 155 development of severe COVID-19 (Fig. 3) . Another study showed that the seroconversion -the time from vaccination to the availability of virus 288 specific antibodies in the blood -rate for CVOID-19 was only 55% in cancer patients following one dose 289 of Pfizer-BioNTech, though it reached 100% in the control group (25 subjects) [129] . That being said, 290 these promising observations have been confounded by reports that some cancer patients fail to 291 respond to the SARS-CoV-2 vaccine at all (Fig. 4) . These poor vaccine specific antibody responses could 292 result from suboptimal T/B-cell priming and collaboration that is a consequence of the fibrosis (driven by 293 excessive TGF-β) which disrupts the LN architecture. Further studies to understand the mechanisms that 294 underlie poor immune response to vaccine in SARS-CoV-2 infected cancer patients are still needed. 295 Given the poor COVID-19 vaccine efficacy in cancer patients, it becomes increasingly important 296 to find alternate means of treating SARS-CoV-2 infected cancer patients (Fig. 4) . 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Cancer (1) is heterogenous depending 701 on the tumor micro environment: hot or cold (2), and the susceptibility of patients with cancer to Four major signaling pathways that are common and 703 impaired in both diseases are: cytokine, type-I IFN, androgen receptor, and immune checkpoint signaling 704 pathways (4). These impairments in signaling pathways lead to cytokine storm that consequently ends 705 up on acute respiratory distress syndrome (ARDS) Course of infection of SARS-CoV-2 712 (1) -influenced by differential expression of ACE2 and TMPRSS2 in hot vs cold cancers -can lead to 713 poor outcome of COVID-19 in hot vs cold cancer patients. Immune responses and development of 714 immunity against SARS immune responses in hot vs cold cancers -can lead to poor outcome of COVID-19 in hot vs cold cancer 716 patients. Impact of therapies (3) -influenced by immunotherapy as well as chemotherapy in hot vs cold 717 cancers -can lead to poor outcomes of COVID-19 Treatments to enhance the immune response against SARS-CoV-2 infection in cancer patients CoV-2 infect individuals with cancers (1) and SARS-CoV-2 infected individuals develop COVID-19 COVID-19 vaccine is the first strategy to protect immunocompromised individuals, particularly cancer 723 patients, from SARS-CoV-2 infection (3) anti-IL-1 (i), anti-IL-6 (ii), other immune modulators (iii), and anti-PD