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Advances in Radiotherapy
& Nuclear Medicine Advancements and challenges in radioactive iodine-125

5. Immunological aspects of I-125 the upregulation of PD-L1 expression at this stage reflects
brachytherapy the immune response driven by infiltrating CD8+ T
cells secreting IFN-γ. Consequently, PD-L1 expression
In vitro and clinical studies have confirmed the synergistic on tumor cells during this phase should not solely be
effect between radiation-induced tumor “in situ” vaccine interpreted as an indication of immune suppression within
effect and the remodeling of the immune microenvironment the TIME. Instead, it signifies the promotion of the tumor
when combined with immune checkpoint inhibitor therapy immune response by CD8+ T cells due to radiotherapy.
across various tumor types [66,67] . When combined with Taken together, these observations suggest a correlation
immunotherapy, the objective of radiotherapy extends between the upregulation of PD-L1 expression on tumor
beyond local tumor control. It aims to maximize the body’s cells after I-125 brachytherapy and the heightened
anti-tumor immune response, serving as an adjuvant that presence of infiltrating CD8+ T cells. This mechanism,
produces synergistic effects alongside immunotherapy . which promotes the upregulation of PD-L1 expression
[68]
The changes in the local tumor immune on tumor cells, essentially represents a negative feedback
microenvironment (TIME) and the consequent changes mechanism regulating the body’s immune response.
in systemic immune status following I-125 close-range Unfortunately, tumors exploit this mechanism as a tool
therapy for post-operative local tumors remain unclear. to develop adaptive immune tolerance. Therefore, several
In contrast to EBRT, I-125 brachytherapy offers the studies propose that PD-L1 expression on tumor cells can
advantage of high conformity, enabling the delivery of be used as a marker for the emergence of adaptive immune
high doses to the target area while minimizing damage to resistance following the infiltration of tumor antigen-
the surrounding normal tissues. This protection extends to specific T lymphocytes [70,71] .
radiosensitive lymphoid immune cells in normal tissues, At the same time, when comparing the expression of
safeguarding them from radiation. pSTAT1 before and after treatment (pSTAT1 being the
At present, several relevant studies have focused downstream product resulting from the combination of
on prostate cancer. Following I-125 brachytherapy for IFN and its receptor), it was found that individuals who
prostate cancer, there is a significant increase in the density responded effectively to PD-1/PD-L1 blockade treatment
of CD3+, CD4+, and CD8+ T cells within the tumor exhibited markedly increased pSTAT1 expression
microenvironment. More importantly, the expression before and after treatment, in contrast to those who did
rate of PD-1+ T cells also shows a significant increase not respond to treatment. This finding suggests that
compared to pre-seed implantation levels. In one study, individuals who responded effectively to PD-1/PD-L1
eight patients who were PD-1 negative before treatment blockade treatment display elevated levels of both IFN-γ
became positive after undergoing brachytherapy, and the and PD-L1 expression. Hence, it implies that IFN-γ plays a
density of infiltrating PD-1+ T cells increased significantly. role in promoting the expression of PD-L1.
Therefore, I-125 brachytherapy can induce the generation of Combining insights from previous studies, a significant
the tumor antigen-specific PD-1+CD8+ T cells, recruiting increase in CD4+ T cell expression was observed in both
them into the tumor microenvironment. In addition, the peripheral blood and the tumor microenvironment
study found that after I-125 brachytherapy, the number following I-125 brachytherapy for prostate cancer.
of CD3+ T cells, CD4+ T cells, and natural killer cells in Notably, CD4+ T cell expression within the tumor
the peripheral blood of prostate cancer patients increased microenvironment was significantly higher than that of
significantly. Although the number of CD8+ T cells did not CD8+ T cells. CD4+ T cells exert their anti-tumor immune
exhibit a significant change, the CD4/CD8 ratio increased function through various mechanisms, including direct
significantly. tumor immune effects by regulating the expression of
At present, the role of radiotherapy in promoting the perforin and granzyme, indirect modulation of the tumor
infiltration of CD8+ T cells into tumor lesions is widely microenvironment to coordinate anti-tumor immunity,
recognized, suggesting the recruitment of tumor antigen- and their role in immunotherapy . The generation of
[72]
specific CD8+ T cells into the tumor microenvironment . CD8+ memory T lymphocytes relies on the assistance
[69]
Following I-125 brachytherapy, there is a significant of CD4+ T cells. Studies have indicated that, even when
increase in PD-L1 expression on prostate cancer cells. PD-1/PD-L1 blockade therapy is ineffective, CD4+ T cells
This increase in PD-L1 expression is associated with the can re-exert the anti-tumor immune response of CD8+
infiltrating CD8+ T cells in the tumor microenvironment, T cells . In a mouse model of prostate cancer, where
[73]
particularly those secreting interferon (IFN)-γ, which radiation therapy was combined with immunotherapy,
promotes PD-L1 expression on tumor cells. As a result, a notable increase in tumor-specific CD4+ T cells

Volume 1 Issue 2 (2023) 7 https://doi.org/10.36922/arnm.0914