がん幹細胞（cancer-stem cell or cancer-stem like cell, CSC）の存在が様々な腫瘍で確認されている．がん組織における割合は極めて少ないものの，これらの細胞は生体内における腫瘍増殖の起始点となり，再発・転移の原因として注目されている．CSCはがん根治を考えるうえで欠かせない細胞成分であるが，non-CSCに比べ化学療法や放射線療法さらに分子標的薬といった治療法に耐性を示すことが問題であった．当研究室では，CSCを標的とした免疫応答解析のために，これまで抗原性に優れたがん幹細胞特異抗原を複数同定している．ペプチド誘導した細胞傷害性T細胞（CTL）はいずれのケースでもin vivoモデルで効果的に腫瘍増殖を抑制する．即ち，CTLはCSCを識別可能であり，同時にCSCを標的とした効果的ながん免疫治療の開発が期待できる．本稿では明らかとなってきたがん幹細胞免疫応答に焦点をあて，CSCの単離法とCTL抗原の同定について概説する．
Efficacy of immune checkpoint inhibitors such as PD-1 antibody for colorectal cancer remains to be proved except in microsatellite-instability-high (MSI-H) cases. While the objective response rate of MSI-H cases was 40%, that of microsatellite-stable (MSS) cases was 0%, showing that response rate to immune checkpoint inhibitors varies even among the microsatellite status. Some possible mechanisms that confer each patient variation in the response to immunotherapy should be considered. We focused on the combination of inter-patient heterogeneity and intra-tumor heterogeneity as a determining factor of immune reaction. An example of intra-tumor heterogeneity is the low expression of tumor antigen by CD271+ cells in melanoma. It is not surprising that similar mechanism exists in CRC. Other related intra-tumor heterogeneity includes EMT and autophagy, both molecular mechanisms that are thought to promote immune-evading phenotype. Besides the microsatellite status, inter-patient heterogeneity in response to tumor immunity includes hypermutator phenotype, which is driven by POLE mutation, intrinsic cytokine production, and microbiota in the gut.
Immune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.
When patients with autoimmune diseases, such as rheumatoid arthritis (RA), are treated with potent immunosuppressive therapy, the risk of opportunistic diseases inevitably increases. If patients have the misfortune to suffer from both opportunistic and active autoimmune diseases, correct diagnosis could sometimes be difficult since both diseases have inflammatory nature. The choice of treatment is another challenge in that aggressive immunosuppressive therapy can fuel the opportunistic infection. Here we report a case of RA patient with new onset rheumatoid vasculitis that was diagnosed in the process of treatment of Pneumocystis jirovecii pneumonia.