Functional studies of pathogen-specific T cell responses in patients with chronic lymphocytic leukemia

<p dir="ltr">CLL is the most common type of leukemia in adults and remains an incurable malignancy. Patients with CLL often suffer from non-malignant complications, particularly recurrent infections, which have been highlighted in recent years by the exceptionally high mortality rates during the COVID-19 pandemic. Increasing evidence indicates that T cells in CLL patients become functionally exhausted, potentially contributing to their impaired control of pathogenic infections. To this end, this thesis investigated the pathogen-specific T cell response, functionality, and characteristics across patients with varying tumor burden, different targeted therapies, and diverse vaccination and infection histories, against a broad spectrum of pathogens, including the most common bacteria and viruses.</p><p dir="ltr">In <b>Study I</b>, we assessed the magnitude and functionality of both bacteria- and virus-specific CD4+ T cells and characterized their phenotypic signatures before and after BTKi therapy. We demonstrated that the impaired functionality of CD4+ T cells was largely irreversible even after a reduction in tumor burden. Moreover, these cells progressively lost their stem-like memory subset during CLL progression.</p><p dir="ltr">In <b>Study II</b>, we investigate the phenotype and functional property of virus- specific CD8+ T cells. Although the overall magnitude of these responses was largely preserved in CLL patients, their functional capacity remained persistently impaired and did not recover after tumor burden reduction. In parallel, these cells exhibited a gradual loss of self-renewing characteristics and became confined to a terminal effector state despite effective tumor reduction by next- generation BTKi therapy.</p><p dir="ltr">In <b>Study III</b>, we detected both humoral and cellular responses to variants of the SARS-CoV-2 spike antigen. We first showed the system and mucosal vaccine response in patents with long-term next-generation of zanubrutinib treatment.</p><p dir="ltr">In <b>Study IV</b>, we demonstrated that memory T cells remained capable of recognizing both the ancestral strain and the highly mutated BA.2.86 variant of COVID-19, in both healthy individuals and patients with CLL.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Jinghua Wu</b>, Yu Gao, Curtis Cai, Maria Andersson, Rokeya Sultana Rekha, Takuya Sekine, Sarah Adamo, Kia Heimersson, Oriana Jesus Ribeiro, Marzia Palma, Peter Bergman, Rula Zain, C. I. Edvard Smith, Anders Österborg, Marcus Buggert. Systemic pathogen-specific CD4+ T cell dysfunction persists despite selective BTK inhibition in CLL. [Manuscript]</p><p dir="ltr">II. <b>Jinghua Wu</b>, Curtis Cai, Maria Andersson, Mily Akhirunnesa, Thomas R. Müller, Takuya Sekine, Kia Heimersson, Akshaya Vidhya, Marzia Palma, Rula Zain, C. I. Edvard Smith, Yu Gao, Anders Österborg, Marcus Buggert. BTKi therapy uncouples tumor control from virus-specific CD8+ T cell functional recovery in CLL. [Manuscript]</p><p dir="ltr">III. Andersson M*, <b>Wu J*</b>, Wullimann D, Gao Y, Aberg M, Muschiol S, Healy K, Naud S, Bogdanovic G, Palma M, Mellstedt H, Chen P, Ljunggren HG, Hansson L, Sallberg Chen M, Buggert M, Ingelman-Sundberg HM, Osterborg A. Local and Systemic Immunity During Five Vaccinations Against SARS-CoV-2 in Zanubrutinib-Treated Patients With Chronic Lymphocytic Leukemia. J Hematol. 2023 Aug;12(4):170-175.<br><a href="https://doi.org/10.14740/jh1140">https://doi.org/10.14740/jh1140<br></a><br></p><p dir="ltr">IV. Müller TR*, Gao Y*, <b>Wu J,</b> Ribeiro O, Chen P, Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Vesterbacka J, Akber M, Söderdahl G, Smith CIE, Loré K, Chen MS, Ljungman P, Ingelman-Sundberg HM, Ljunggren HG, Österborg A, Sette A, Grifoni A, Aleman S, Buggert M. Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant. Cell Host Microbe. 2024 Feb 14;32(2):156-161.e3. <br><a href="https://doi.org/10.1016/j.chom.2023.12.010">https://doi.org/10.1016/j.chom.2023.12.010</a><br></p><p dir="ltr">*These authors contributed equally</p>