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Wong et al. Cancer Drug Resist 2023;6:768-87 https://dx.doi.org/10.20517/cdr.2023.58 Page 780

[111]
suggested that the increase in MDSCs was associated more often with non-responders . Interestingly, the
γ isoform of PI3K has been noted to be highly expressed in MDSC cells in a study of several cancer types,
[113]
[112]
including breast cancer , and selectively inhibiting it can help to re-establish sensitivity to ICIs .
Another important group of cells present in the TME that promote immunosuppression and play a role in
resistance to immunotherapy are TAMs, which consist of M1 and M2 macrophages . M1 macrophages
[114]
are mainly involved in antitumour immunity, while M2 macrophages are pro-tumourigenic. The
accumulation of TAMs is regulated by cytokines, such as chemokine ligand 2 (CCL2), which was
demonstrated by Qian et al. in their study using breast cancer- bearing murine model , as well as colony-
[115]
stimulating factor-1 (CSF-1). It was observed to be correlated with increased macrophage infiltration and
[116]
more frequent metastases in breast cancer patients . Indeed, studies that evaluated CSF-1 receptor
inhibition in combination with ICI treatment showed synergy of both agents and promising tumour
regression, suggesting that CSF-1 receptor inhibitors can help to overcome tumour resistance to
immunotherapy [117,118] .

Besides individual populations of cells, the make-up of various cytokines present in the TME is also
important in immune cell recruitment, activation, and proliferation by its balance of both stimulatory and
suppressive effects . For example, cytokines such as transforming growth factor β (TGF-β) induce
[119]
[120]
immunosuppression by upregulating Tregs and inhibiting cytotoxic T lymphocytes . Tumour cells also
express ecto-5’-nucleotidase (CD73), which is an enzyme that dephosphorylates adenosine monophosphate
[121]
(AMP), forming adenosine . Adenosine is a potent immunosuppressor that binds to A2A receptors found
[123]
on lymphocytes and suppresses its function . Breast cancer cells have been shown to express CD73 ,
[122]
and its expression appears to be regulated by the estrogen receptor (ER), whereby the loss of ER enhances
[124]
the expression of CD73 . A proof of concept study confirmed that anti-CD73 antibody therapy can trigger
adaptive antitumour immunity and inhibit metastasis in breast cancer .
[125]
Upregulation of other immune checkpoints
Resistance to ICIs can also be achieved via upregulation of other immune checkpoints such as T-cell
immunoglobulin, mucin domain-3 protein (TIM-3), LAG-3, V-domain immunoglobulin suppressor of
T-cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and T-cell immunoreceptor tyrosine-
based inhibition motif domain (TIGIT) [108,126-128] . The co-expression of multiple immune checkpoints has
[129]
been demonstrated to be associated with T cell exhaustion, and subsequently resistance to ICIs .
Targeting these alternative pathways represents potential therapeutic options for overcoming drug
resistance to ICIs. Although most studies evaluating such combination strategies have been in other tumour
types such as melanoma and NSCLC [130-132] , these are still relevant in breast cancers as epigenetic
modifications resulting in upregulation of multiple immune checkpoints such as PD-L1, CTLA-4, TIM-3,
and LAG-3 have been observed, and correlated with poorer patient prognosis in a study of breast cancer
patients . A study that specifically included breast cancer patients was a phase I study of LAG525, a
[133]
monoclonal antibody blocking the binding of LAG-3 to MHC-II in combination with spartalizumab (an
[134]
anti-PD-1 antibody) in patients with advanced malignancies, which showed durable responses . In
particular, 2 out of 5 patients with advanced TNBC showed a response, and in TNBC tumour biopsies, a
trend in the conversion of immune-cold to immune-activated biomarker profiles was reported .
[134]

CONCLUSION: CHALLENGES AND FUTURE DIRECTIONS
Aside from resistance mechanisms to ICIs, there are also many unresolved and unanswered questions that
have limited the use of ICIs in breast cancer. These include identifying the best predictive and prognostic
biomarkers to guide treatment, evaluating the optimal duration of ICIs in the neoadjuvant/adjuvant setting,