Discussion
Chen et al. reported that RT
plays a role in antigen spread, which leads to T-cell immune activation
in the cancer immunity cycle (9). Moreover, according to the review by
Sharabi et al., the roles of RT in cancer immunology are as follows: 1)
radiation induces changes to the tumor cell immunophenotype, 2)
radiation enhances cross-presentation of tumor antigens, and 3)
radiation combined with an ICI increases tumor cell susceptibility to
immune-mediated cell death (2). We have reported that RT induced
cancer/testis antigen-specific cytotoxic T-cell activation in ESCC
patients treated with chemo-RT, and multi-antigen-specific T-cell
responses were observed in some patients (4).
Already, the concept of ICI+RT (so-called immunoradiotherapy) has been
clinically proven in non-small-cell lung cancer (NSCLC) (10,11). The
anti-PD-L1 antibody durvalumab administered every 2 weeks for 12 months
after radical chemo-RT for stage 3 NSCLC (PACIFIC trial) improved the
progression-free survival rate by about 20% at 1 year (10) and the
overall survival rate by about 15% at 4 years (11). This ICI+RT regimen
has already become the standard therapy for stage 3 NSCLC. At present,
many clinical trials of ICI+RT are underway for cancers at other sites,
including esophageal cancer (12).
Regarding the adverse effects of ICI+RT, severe (grade 3 or higher)
adverse effects were not increased in the PACIFIC trial. Furthermore,
Sha et al. performed a systemic review and meta-analysis, and reported
comparable grade 3–4 toxicity using ICI+RT compared with ICI alone in
CNS melanoma, NSCLC, and prostate cancer, and they concluded that ICI+RT
was safe (13).
A change in the TCR/BCR repertoire after treatment is proof of a
treatment-induced immunoresponse. Changes in the TCR and BCR repertoires
by treatment have already been reported (14,15). Moreover, changes in
the TCR repertoire by RT and chemo-RT have been reported in myeloma
(14), and head and neck cancer (15). The usefulness of analyzing the TCR
repertoire to detect the efficacy of anti-PD-1 antibody (clonality [1
– Pielou’s evenness] (16) and frequency of the top 30 most frequent
clonotypes: 17)) and the BCR repertoire to detect the efficacy of
autologous cellular immunotherapy (clonality (18)) has been reported.
Analysis of the TCR and BCR repertoires may facilitate the dissection
and understanding of the immune response in human cancer patients and
may be useful as a biomarker of RT or ICI+RT. In our patient, the BCR
repertoire ranking greatly changed with RT and the TCR repertoire also
changed. All diversity indexes for both the TCR and BCR repertoires
decreased after RT. These changes in the TCR and BCR repertoires may be
associated with RT-induced tumor-specific anti-tumor immunity, resulting
in the abscopal effect in the patient with nivolumab-resistance. In
other words, it is possible that further antigen spread by RT may
retrieve the effect of nivolumab in patients with nivolumab-resistance.
Since each metastatic tumor is not the same (homogenous), RT to another
metastatic tumor may induce new or more immune responses (19).
In our patient, RT was performed as a palliative local treatment after
disease progression during nivolumab treatment, and the abscopal effect
was observed. Changes in the TCR and BCR repertoires were observed after
RT, and these were assumed to be a part of the mechanism of the abscopal
effect. The findings in this patient suggest that ICI+RT can be a
promising treatment approach, even for patients with ICI-resistant
cancer.