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Page 675 Gurska et al. Cancer Drug Resist 2023;6:674-87 https://dx.doi.org/10.20517/cdr.2023.39

leukemia in adults. Long-term outcomes for AML have not significantly improved over the past few
decades, with a suboptimal 5-year overall survival rate of 30% for AML patients ages 20 and older and less
[1]
than 10% for AML patients ages 65 and older . The current standard of care approaches for AML,
including induction chemotherapy, combinations of venetoclax with hypomethylating agents, and stem cell
transplantation, still yield high relapse rates with significant toxicities. Therefore, new less toxic therapeutic
approaches need to be developed to improve survival and prevent relapse in this disease.

Hematopoiesis is the process through which all mature blood cell lineages are generated from
hematopoietic stem cells (HSCs), which have the capacity to both self-renew and differentiate. Without
proper regulation of their cell-intrinsic and cell-extrinsic cues (primarily signaling pathways, transcription
factors, and epigenetic regulators), HSCs and downstream progenitors can acquire unlimited self-renewal
potential at the expense of differentiation, as well as increased proliferation and survival, leading to AML
development . AML blasts develop from aberrant HSCs or progenitors - termed the leukemic stem cell
[2-5]
(LSC). LSCs are undifferentiated blood cells that have pathologic self-renewal properties and lead to
abnormal blood production. Phenotypically, LSCs share some of the same cell surface markers as HSCs, but
unique LSC and pre-LSC gene expression signatures have been identified by high throughput
sequencing . Like HSCs, LSCs are primarily quiescent and are therefore resistant to chemotherapy and
[6-9]
other therapies that target actively cycling cell populations [3,10] . Yet, the standard induction “7 + 3”
chemotherapy regimen remains the preferred up-front treatment strategy for AML patients who are fit
enough to tolerate intensive induction therapy, which, in addition to sparing LSCs, results in various
toxicities, such as pancytopenia and infection [11,12] . This has led to enhanced research efforts to identify novel
therapies that target the LSC population while sparing healthy HSCs to improve AML patient outcomes.

However, in addition to the cell-autonomous mechanisms AML cells have employed to persist despite the
cytotoxic effects of chemotherapy, AML cells have developed additional ways to persist despite treatment,
including resistance mechanisms to targeted therapies and immune evasion. Notably, AML cells employ
several mechanisms, such as reliance on immune cells, to establish an immunosuppressive environment to
ensure their survival. This is accomplished through the reduction of cytotoxic and effector T and NK cells,
increased T cell exhaustion, and recruitment of immunosuppressive populations such as regulatory T cells,
[13]
myeloid-derived suppressor cells (MDSCs), and M2 macrophages . Importantly, it has been reported that
the number of effector and cytotoxic T cells, termed tumor-infiltrating lymphocytes (TILs), present in the
bone marrow can be a prognostic marker for overall survival and leukemia-free survival . In addition,
[14]
increased numbers and function of regulatory T cells in both the peripheral blood and bone marrow of
AML patients have been reported, with bone marrow-resident regulatory T cells exhibiting more
immunosuppressive effects on CD4+ effector T cell proliferation . A lower frequency of regulatory T cells
[15]
was found to correlate with complete remission rates in AML patients, while a higher frequency was
[15]
observed in patients who relapsed .

Despite advances in immunotherapies in solid tumors and some lymphoid malignancies, AML has been
particularly difficult to treat with immunotherapies, primarily due to poor T cell recruitment to the bone
marrow and because LSCs are immune privileged. Because even with the current therapeutic options, AML
remains a lethal disease with a suboptimal long-term survival rate, it is imperative to identify and exploit the
mechanisms by which AML cells evade immune detection to unleash the potential benefits of
immunotherapy in AML treatment. This review summarizes the roles of T cells in the immune response,
and highlights the challenges that AML cells pose to the efficacy of ICIs by evading T cell detection.