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Author Manuscript Published OnlineFirst on June 18, 2020; DOI: 10.1158/0008-5472.CAN-20-1420 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 How Tumor Cell Dedifferentiation Drives Immune Evasion And Resistance to 2 Immunotherapy 3 4 Jinyang Li1,2,3, Ben Z. Stanger1,2,3,* 5 6 1Department of Medicine, 2Department of Cell and Developmental Biology, 3Abramson 7 Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, 8 USA. 9 *Correspondence: [email protected] (Ben Z. Stanger) Tel: 215-746-5560 10 11 Keywords (2-6 keywords) 12 Tumor immunology, immune evasion, tumor dedifferentiation, cell plasticity 13 14 Abstract 15 Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. 16 While tumor antigens are needed for effective immunotherapy, a favorable tumor 17 immune microenvironment is also critical. In this review, we discuss emerging evidence 18 that tumor cells exploit cellular plasticity and dedifferentiation programs to avoid immune 19 surveillance, which in turn drives metastatic dissemination and resistance to 20 immunotherapy. A deeper understanding of these programs may provide novel 21 opportunities to enhance the efficacy of existing immunotherapies. 22 23 Running Title: Cellular plasticity facilitates immune avoidance 24 1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2020; DOI: 10.1158/0008-5472.CAN-20-1420 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 25 26 Tumor immunotherapy and resistance mechanisms 27 Studies over the past two decades have uncovered a crucial role for the immune 28 system in tumor biology (1). Immune cells interact with and functionally influence tumor 29 cells at every stage of tumor development and metastatic dissemination (1–3). 30 Therapeutic interventions enhancing immune cell functions – including chimeric antigen 31 receptor (CAR) T cell-based treatments and immune checkpoint blockade (ICB) – have 32 revolutionized the clinical care of cancer patients with various types of malignancies 33 (1,4–6). Despite these remarkable successes, most cancers are refractory to 34 immunotherapy as a result of immune evasion of tumor cells (7–11). Moreover, immune 35 evasion is an important step in the colonization of disseminated and dormant tumor 36 cells in distant organs (2,3,12). Because tumor immune evasion leads to poor clinical 37 outcomes by promoting therapy resistance and metastatic outgrowth, a deeper 38 understanding of the underlying molecular and cellular mechanisms is needed. 39 Tumor cells use various strategies to evade immune surveillance (13,14). These 40 include: (i) down-regulation of the antigen presentation machinery (15–18), (ii) silencing 41 the expression of tumor associated antigens (19,20), (iii) dysregulation of tumor cell 42 intrinsic interferon signaling pathways (21–25), (iv) recruitment of immunosuppressive 43 cells (e.g. regulatory T cells and suppressive myeloid cells) to establish an “immune- 44 privileged” microenvironment (26–29), (v) upregulation of immune suppressive 45 molecules (e.g. PD-L1) (30–32), and (iv) metabolic activity of tumor cells (e.g. 46 production of prostaglandin E2) (33–38). Conveniently (for the tumor cells), many of 47 these immune-evading adaptations are driven by the very oncogenic signaling 48 pathways that provide tumors with their enhanced growth and proliferation properties 2 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2020; DOI: 10.1158/0008-5472.CAN-20-1420 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 49 (e.g. Wnt, mTOR, MYC, and Kras signaling) (13,14,32,39–46). This, in turn, begs an 50 obvious question: What biological properties link oncogenic signaling with immune 51 regulation? One answer to this question, supported by several recent studies, is that 52 such signaling can simultaneously alter cellular differentiation states of tumor cells as 53 well as their recognition by the immune system. 54 55 Tumor cell plasticity and dedifferentiation drives immune evasion 56 Cellular plasticity – defined as a dramatic shift in cellular phenotype – is commonly 57 observed in various types of malignancies, where it contributes to tumor progression 58 and resistance to therapeutic interventions (47–51). One manifestation of plasticity in 59 tumors is dedifferentiation, in which tumor cells lose their specialized properties and 60 take on less differentiated phenotypes reminiscent of early embryonic development or 61 regenerative processes (52). Loss of differentiation is known to be associated with 62 increased tumor cell invasiveness and drug resistance (49–51), but there is growing 63 evidence that tumor cell dedifferentiation is also coupled to immune surveillance. 64 Studies in melanoma, for example, have shown that tumor cell dedifferentiation – 65 and adoption of a stem- or progenitor-like phenotype – leads to an escape of immune 66 recognition by adoptively transferred T cells in both preclinical mouse models and 67 patients (20,53). Two factors contribute to this immune-privileged state: (i) a loss of 68 differentiation-associated antigens (20,53) and (ii) dedifferentiation-associated 69 transcriptional changes that result in the recruitment of immunosuppressive myeloid 70 cells (54). Moreover, a study published earlier this year linked dedifferentiation of 71 melanoma cells with resistance to ICB in both preclinical mouse models and cancer 3 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2020; DOI: 10.1158/0008-5472.CAN-20-1420 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 72 patients (55). Thus, there is ample data to support a connection between tumor cell 73 dedifferentiation and immune evasion in this lethal form of skin cancer. 74 There is also evidence for such a connection in other tumor types. In squamous 75 cell carcinoma, for example, dedifferentiated tumor cells acquire stem-like properties 76 and express the immune modulating molecule CD80, leading to escape from immune 77 attack (56). Similarly, dedifferentiated tumor initiating cells can evade immune 78 surveillance by dysregulation of PD-L1 or NKGD2 (57,58). Moreover, single cell 79 analysis has revealed that lung cancer cells possess heterogeneous differentiation 80 states that correspond to various stages of lung development. These distinct states are 81 associated with different sensitivities to immune surveillance and metastatic colonization 82 capacity, a consequence of differential expression of natural killer cell and T cell 83 recognition and regulatory molecules (59). Interestingly, one recent study showed that 84 metastasis-initiating colorectal cancer cells possess molecular features of regenerative 85 epithelial cells (60). These studies highlight potential molecular connections linking 86 tissue regeneration and immune surveillance, given that tissue damage, compensatory 87 regeneration, and the associated inflammatory response may all promote tumor 88 progression. Such an idea is in line with studies from multiple tumor types that epithelial 89 mesenchymal transition or EMT (another form of altered cellular differentiation) leads to 90 immune evasion through various molecular mechanisms, including increases in immune 91 inhibitory molecules and decreases in the antigen presentation machinery (49,61–66). It 92 is also important to note that dedifferentiation of tumor cells may cause increased 93 expression of developmental antigens such as cancer testis antigens, which may have 94 an opposing effect on immune surveillance (67–69). Together, these studies indicate 4 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 18, 2020; DOI: 10.1158/0008-5472.CAN-20-1420 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 95 that tumor cell dedifferentiation promotes immune evasion through distinct, but related, 96 molecular mechanisms. 97 98 Conserved immune evasion mechanisms in normal cells 99 Why might acquisition of a stem- or progenitor-like state – the phenotypic consequence 100 of dedifferentiation – lead to immune evasion? One possibility is that tumor cells are 101 simply recapitulating an evolutionarily conserved program that protects stem cells from 102 immune attack. It is known that certain quiescent tissue-resident stem cells evade 103 detection and killing by the innate and adaptive immune system by downregulating 104 molecules involved in antigen presentation (70). Interestingly, one recent study provided 105 evidence that disseminated pancreatic tumor cells in the liver can evade T cell mediated 106 immune surveillance when they reside in a quiescent state (71). Likewise, other studies 107 have highlighted the function of slow cycling and less differentiated cancer stem cells in 108 shaping the tumor immune microenvironments (72). Collectively, these findings indicate 109 that dedifferentiation-associated changes in cell proliferation may regulate the
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